15-80168263-G-T

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1 PM2 PP3_Strong PP5_Very_Strong

The NM_000137.4(FAH):c.554-1G>T variant causes a splice acceptor 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
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:15 O:1
• Conservation: PhyloP100: 8.99

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]

ACMG classification

Verdict is Pathogenic. Variant got 22 ACMG points.

• PVS1: Splicing 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
• 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 15-80168263-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	HGVSp	Effect	#exon/exons	MANE	UniProt
FAH	NM_000137.4	c.554-1G>T		splice_acceptor_variant		ENST00000561421.6
FAH	NM_001374377.1	c.554-1G>T		splice_acceptor_variant
FAH	NM_001374380.1	c.554-1G>T		splice_acceptor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAH	ENST00000561421.6	c.554-1G>T		splice_acceptor_variant		1	NM_000137.4	P1

Frequencies

GnomAD3 genomes AF: 0.000106 AC: 16 AN: 150484 Hom.: 0 Cov.: 31

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: 38 AN: 249864 Hom.: 0 AF XY: 0.000148 AC XY: 20 AN XY: 135178

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.: 0 Cov.: 36 AF XY: 0.000220 AC XY: 159 AN XY: 723500

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: 16 AN: 150592 Hom.: 0 Cov.: 31 AF XY: 0.0000818 AC XY: 6 AN XY: 73360

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.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tyrosinemia type I Pathogenic:11 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 31, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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	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 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1996	- -
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	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	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	Mar 05, 2022	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 07, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 03, 2022	PM2, PM3, PS4, PVS1 -
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	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Mar 03, 2021	PVS1, PM2, PM3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Uncertain	0.040
Cadd	Pathogenic	33
Dann	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0	A;A;A;A
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

Other links and lift over

dbSNP: rs80338895; hg19: chr15-80460605;