15-80168263-G-T

Position:

chr15-80168263-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000137.4(FAH):c.554-1G>T variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000199 in 1,604,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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 0.00011 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

FAH
NM_000137.4 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:17O:1

Conservation

PhyloP100: 8.99

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:

FAH (HGNC:):

FAH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 6.6, offset of -34, new splice context is: ttctgtggcctcactcacAGcac. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 15-80168263-G-T is Pathogenic according to our data. Variant chr15-80168263-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 11874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-80168263-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
FAH	NM_000137.4 linkuse as main transcript	c.554-1G>T	splice_acceptor_variant, intron_variant	ENST00000561421.6	NP_000128.1	P16930-1A0A384P5L6
FAH	NM_001374377.1 linkuse as main transcript	c.554-1G>T	splice_acceptor_variant, intron_variant		NP_001361306.1
FAH	NM_001374380.1 linkuse as main transcript	c.554-1G>T	splice_acceptor_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.554-1G>T		splice_acceptor_variant, intron_variant		1	NM_000137.4	ENSP00000453347.2		P16930-1

Frequencies

GnomAD3 genomes

AF:

0.000106

AC:

AN:

150484

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000236

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000152

AC:

AN:

249864

Hom.:

AF XY:

0.000148

AC XY:

AN XY:

135178

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000220

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000209

AC:

304

AN:

1453514

Hom.:

Cov.:

AF XY:

0.000220

AC XY:

159

AN XY:

723500

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000793

Gnomad4 NFE exome

AF:

0.000237

Gnomad4 OTH exome

AF:

0.000399

GnomAD4 genome

AF:

0.000106

AC:

AN:

150592

Hom.:

Cov.:

AF XY:

0.0000818

AC XY:

AN XY:

73360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000236

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000173

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000296

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tyrosinemia type I

Pathogenic:11Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	NM_000137.2(FAH):c.554-1G>T(aka IVS6-1G>T) is classified as pathogenic in the context of tyrosinemia type I. Sources cited for classification include the following: PMID 8557261, 23348723, 21752152, 12203990, and 9633815. Classification of NM_000137.2(FAH):c.554-1G>T(aka IVS6-1G>T) is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Feb 12, 2024	Criteria applied: PVS1,PM3_VSTR,PM2_SUP,PP4 -
not provided, no classification provided	literature only	GeneReviews	-	Southern European-specific pathogenic variant resulting from founder effect or genetic drift [Angileri et al 2015]. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change affects an acceptor splice site in intron 6 of the FAH gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs80338895, gnomAD 0.03%). Disruption of this splice site has been observed in individual(s) with tyrosinemia type 1 (PMID: 8829657, 11476670, 12203990). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS6-1. ClinVar contains an entry for this variant (Variation ID: 11874). Studies have shown that disruption of this splice site results in skipping of exon 8 and introduces a premature termination codon (PMID: 8557261, 11476670). The resulting mRNA is expected to undergo nonsense-mediated decay. 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	Revvity Omics, Revvity	Mar 31, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1996	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The FAH c.554-1G>T variant, also known IVS6-1G>T, occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.554-1G>T variant is a well described common FAH pathogenic variant, accounting for over 16% of tyrosinemia disease-associated alleles worldwide (Sniderman King et al. 2006; Angileri et al. 2015). Across a selection of the available literature, the c.554-1G>T variant has been reported in at least 71 patients including in 48 in a homozygous state, in 16 in a compound heterozygous state, and in seven in a heterozygous state in whom a second variant has not been detected (Rootwelt et al. 1996; Timmers et al. 1996; Bergman et al. 1998; Dreumont et al. 2001; Arranz et al. 2002; la Marca et al. 2011; Dursun et al. 2011; Laszlo et al. 2013; van Vliet et al. 2015; Mayorandan et al. 2014). The variant was absent from 270 control chromosomes but is reported at a frequency of 0.00035 in the European American population of the Exome Sequencing Project. Functional studies have shown that the variant results in an absence of FAH protein, undetectable FAH activity in patient liver cells and fibroblasts, and a complex pattern of aberrant splicing (Bergman et al. 1998; Arranz et al. 2002; Angileri et al. 2015). Based on the collective evidence and the potential impact of splice acceptor variants, the c.554-1G>T 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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 12, 2017	Variant summary: The FAH c.554-1G>T variant involves the alteration of a conserved intronic nucleotide located in the canonical splice site at the junction of intron6/exon7 border. Mutation taster predicts a damaging outcome for this variant along with 5/5 splice prediction tools predicting the variant to eliminate the splice acceptor site. This variant was found in 13/121368 control chromosomes at a frequency of 0.0001071, which does not exceed the estimated maximal expected allele frequency of a pathogenic FAH variant (0.0025). This variant has been reported in several Tyrosemia type 1 patients either in homozygosity or compound heterozygosity with other potentially pathogenic FAH variant indicating pathogenicity of this variant. RT-PCR products amplified from total RNA extracted from cultured fibroblasts of a patient homozygous for IVS6-1G->T showed aberrant splicing pattern further supporting its deleterious impact. In addition, another variant affecting the same position, c.554-1G>C is reported in HGMD as a disease causing mutation. Moreover, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Considering all evidence, the variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 06, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Feb 21, 2022	ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderate, PM3 very strong -

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Mar 03, 2021	PVS1, PM2, PM3 -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	FAH: PM3:Very Strong, PVS1, PM2, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 07, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2023	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Also known as IVS6-1 G>T; This variant is associated with the following publications: (PMID: 25087612, 11476670, 23348723, 30414057, 30954369, 29625052, 31980526, 34426522, 31589614, 10073910, 32778825, 22975760, 8557261, 12203990, 8829657, 20301688, 25681080, 8723690) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 03, 2022	PM2, PM3, PS4, PVS1 -

FAH-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 01, 2024

The FAH c.554-1G>T variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant, also referred to in the literature as IVS6-1G>T, has previously been reported to be a common causative variant for tyrosinemia type I (see, for example, Rootwelt et al. 1996. PubMed ID: 8829657; Arranz et al. 2002. PubMed ID: 12203990; Angileri et al. 2015. PubMed ID: 25681080). This variant is reported in 0.037% of alleles in individuals of Latino descent in gnomAD. Variants that disrupt consensus splice acceptor sites in FAH are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

1.0

GERP RS

5.6

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.82

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.77

Position offset: 6

DS_AL_spliceai

0.99

Position offset: 1

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