rs80338901

Positions:

chr15-80180230-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_000137.4(FAH):c.1062+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00038 in 1,602,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00039 ( 0 hom. )

Consequence

FAH
NM_000137.4 splice_donor_5th_base, intron

Scores

Splicing: ADA: 0.9990

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:26U:1O:1

Conservation

PhyloP100: 9.13

Variant links:

Genes affected

FAH (HGNC:3579): (fumarylacetoacetate hydrolase) Predicted to enable fumarylacetoacetase activity. Predicted to be involved in L-phenylalanine catabolic process; homogentisate catabolic process; and tyrosine catabolic process. Predicted to act upstream of or within arginine catabolic process. Located in extracellular exosome. Implicated in tyrosinemia type I. [provided by Alliance of Genome Resources, Apr 2022]

FAH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 15-80180230-G-A is Pathogenic according to our data. Variant chr15-80180230-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11870.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
FAH	NM_000137.4 linkuse as main transcript	c.1062+5G>A	splice_donor_5th_base_variant, intron_variant	ENST00000561421.6	NP_000128.1
FAH	NM_001374377.1 linkuse as main transcript	c.1062+5G>A	splice_donor_5th_base_variant, intron_variant		NP_001361306.1
FAH	NM_001374380.1 linkuse as main transcript	c.1062+5G>A	splice_donor_5th_base_variant, intron_variant		NP_001361309.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAH	ENST00000561421.6 linkuse as main transcript	c.1062+5G>A		splice_donor_5th_base_variant, intron_variant		1	NM_000137.4	ENSP00000453347	P1	P16930-1

Frequencies

GnomAD3 genomes

AF:

0.000269

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000500

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000372

AC:

AN:

242110

Hom.:

AF XY:

0.000349

AC XY:

AN XY:

131680

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.000706

Gnomad NFE exome

AF:

0.000658

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000392

AC:

568

AN:

1450406

Hom.:

Cov.:

AF XY:

0.000361

AC XY:

261

AN XY:

722024

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000197

Gnomad4 FIN exome

AF:

0.000502

Gnomad4 NFE exome

AF:

0.000462

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000269

AC:

AN:

152298

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000500

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000466

Hom.:

Bravo

AF:

0.000234

EpiCase

AF:

0.000382

EpiControl

AF:

0.000474

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:26Uncertain:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tyrosinemia type I

Pathogenic:17Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 06, 2017	The c.1062+5G>A (NM_000137.2) variant in FAH has been reported in 14 homozygous and 2 compound heterozygous individuals with Tyrosinemia type I (Grompe 1993, B liksrud 2012, Mayorandan 2014, and Mannion 2016). This variant has also been rep orted in ClinVar (Variation ID#11870) by multiple laboratories as pathogenic. Th is variant has been identified in 0.065% (41/63,022) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs 80338901). In vitro splicing assays provide evidence that the c.1062+5G>A varian t impacts splicing (Perez-Carro 2014). Biallelic loss of function of the FAH gen e has been associated with Tyrosinemia type I. In summary, this variant meets c riteria to be classified as pathogenic for Tyrosinemia type I in an autosomal re cessive manner based upon functional evidence and its occurrence in individuals with this disease. -
Pathogenic, criteria provided, single submitter	not provided	Institute of Human Genetics, University Hospital of Duesseldorf	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Feb 12, 2024	Criteria applied: PM3_VSTR,PS3,PM2_SUP,PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 02, 2017	Variant summary: The FAH c.1062+5G>A variant involves the alteration of a highly conserved intronic nucleotide in intron 12. Mutation taster tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict a significant impact on normal splicing. Functional studies have shown that this variant leads to aberrant splicing causing either insertion of a 105 base-pair fragment due to a cryptic splice site, or skipping of exon 12, or skipping of both exons 12 and 13 (Hahn_1995, Perez_2014) as well as loss of enzymatic activity in patients cells (Bergeron _2001). The variant of interest has been found in a large and broad control population from ExAC in 48/114466 control chromosomes at an allele frequency of 0.0004193, which does not exceed the estimated maximal expected allele frequency of a pathogenic FAH variant (0.0025). This variant is a known common pathogenic variant that causes tyrosinemia type I and is more commonly found in French Canadian population than the rest of the world (Grompe_1994; GeneReviews). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 12, 2019	NM_000137.2(FAH):c.1062+5G>A is classified as pathogenic in the context of type I tyrosinemia. Sources cited for classification include the following: PMID 23895425, 21752152, 12203990, 22554029, 8318997, 8821854, 8829657 and 8028615. Classification of NM_000137.2(FAH):c.1062+5G>A is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, no assertion criteria provided	curation	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Dec 30, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change falls in intron 12 of the FAH gene. It does not directly change the encoded amino acid sequence of the FAH protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs80338901, gnomAD 0.07%). This variant has been observed in individuals with hereditary tyrosinemia type 1 (PMID: 8318997, 23895425, 26565546). It is commonly reported in individuals of French-Canadian ancestry (PMID: 23193487, 28755192). ClinVar contains an entry for this variant (Variation ID: 11870). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 31, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The FAH c.1062+5G>A variant is one of the most commonly detected pathogenic variants in patients with tyrosinemia type 1. The variant has been reported in at least nine studies in which it is found in a total of 336 patients, including in 47 patients in a homozygous state, in five patients in a compound heterozygous state and in 15 patients in a heterozygous state. The c.1062+5G>A variant was also detected in 11/395 blood spots from anonymous newborns from the Quebec area (Grompe et al. 1993; Grompe et al. 1994; St-Louis et al. 1995; Poudrier et al. 1996; Bergman et al. 1998; Elpeleg et al. 2002; Arranz et al. 2002; Perez-Carro et al. 2014; Mayorandan et al. 2014). The incidence of tyrosinemia is much higher in the Saguenay-Lac-St-Jean region of Quebec than in the rest of the world. In this region the c.1062+5G>A variant was detected in 62/68 patient alleles, and in 86/180 obligate carrier alleles (Grompe et al. 1994; Poudrier et al. 1996). The c.1062+5G>A variant was absent from 91 healthy controls and is reported at a frequency of 0.0007 in the European American population of the Exome Sequencing Project. Functional studies have shown that the variant results in aberrant splicing leading to the skipping of exon 12 of the FAH gene (Arranz et al. 2002; Perez-Carro et al. 2014) and loss of enzyme activity in patient fibroblasts (St-Louis et al. 1995; Bergman et al. 1998). Based on the collective evidence, the c.1062+5G>A variant is classified as pathogenic for tyrosinemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	Thec.1062+5 G>A variant is a common pathogenic variant in patients with tyrosinemia type I from theFrench origin population of Canada or from western Europe (Lazarin GA et al). Functional analysis found that c.1062+5 G>A results in exon skipping of exon 12 (Pérez-Carro R). The variant has been submitted to ClinVar as Pathogenic. Due to the above reasons it has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 31, 2023	- -
not provided, no classification provided	literature only	GeneReviews	-	Northern European and French Canadian-specific pathogenic variant resulting from founder effect or genetic drift [Angileri et al 2015]. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Dec 20, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with tyrosinemia, type I, (MIM#276700). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. RT-PCR of Hep3B cells transfected with a minigene assay indicates that this variant causes exon 12 skipping, although additional products were observed. Due to these products, and the uncertainty regarding the use of minigene assays, the protein outcome of this splicing event is uncertain (PMID: 23895425). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (102 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and has been observed in both homozygous and compound heterozygous individuals with hereditary tyrosinemia (ClinVar, PMID: 30414057. PMID: 31574857). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Pathogenic:8Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	FAH: PM3:Very Strong, PM2, PP3, PP4, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 26, 2019	PS3, PM1, PM2, PP3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 17, 2022	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 06, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 18, 2022	Common pathogenic variant in patients with tyrosinemia type I from the French origin population of Canada or from western Europe (St-Louis et al, 1997); Functional analysis using a minigene found that c.1062+5 G>A results in exon skipping of exon 12 (Prez-Carro et al. 2014); This variant is associated with the following publications: (PMID: 26565546, 8028615, 27876694, 25087612, 23895425, 22975760, 25525159, 8318997, 27794060, 29497141, 29326876, 30414057, 30609409, 31568711, 34426522, 31589614, 33083013, 11754109, 9705236) -

FAH-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 22, 2023

The FAH c.1062+5G>A variant is predicted to interfere with splicing. This variant has been well documented to be causative for tyrosinemia type I (also referred to as IVS12+5G>A; Grompe and al-Dhalimy. 1993. PubMed ID: 8318997; Pérez-Carro et al. 2014. PubMed ID: 23895425) and is particularly prevalent in the French Canadian and Northern European populations (Poudrier et al. 1996. PubMed ID: 8821854; Sheth et al. 2012. PubMed ID: 23193487). Using minigene analysis, the c.1062+5G>A variant was shown to result in exon skipping (Pérez-Carro et al. 2014. PubMed ID: 23895425). This variant is interpreted as pathogenic or likely pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/11870/). This variant is reported in 0.066% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-80472572-G-A). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

0.99

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.78

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.78

Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over