rs121965075

Positions:

chr15-80181048-G-T

Variant summary

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

The ENST00000561421.6(FAH):c.1069G>T(p.Glu357Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000856 in 1,612,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000086 ( 0 hom. )

Consequence

FAH
ENST00000561421.6 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.07

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 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 15-80181048-G-T is Pathogenic according to our data. Variant chr15-80181048-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 11871.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-80181048-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
FAH	NM_000137.4 linkuse as main transcript	c.1069G>T	p.Glu357Ter	stop_gained	13/14	ENST00000561421.6	NP_000128.1
FAH	NM_001374377.1 linkuse as main transcript	c.1069G>T	p.Glu357Ter	stop_gained	14/15		NP_001361306.1
FAH	NM_001374380.1 linkuse as main transcript	c.1069G>T	p.Glu357Ter	stop_gained	14/15		NP_001361309.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAH	ENST00000561421.6 linkuse as main transcript	c.1069G>T	p.Glu357Ter	stop_gained	13/14	1	NM_000137.4	ENSP00000453347	P1	P16930-1

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251462

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135906

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000615

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000863

AC:

126

AN:

1460436

Hom.:

Cov.:

AF XY:

0.0000812

AC XY:

AN XY:

726608

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000109

Gnomad4 OTH exome

AF:

0.0000829

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000137

Hom.:

Bravo

AF:

0.0000718

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tyrosinemia type I

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 09, 2019	NM_000137.2(FAH):c.1069G>T(E357) is classified as pathogenic in the context of tyrosinemia type I. Sources cited for classification include the following: PMID 8028615, 7929843, 7757089, 8076937, 15638932, 8557261 and 8318997. Classification of NM_000137.2(FAH):c.1069G>T(E357) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay 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	Baylor Genetics	Mar 21, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	This sequence change creates a premature translational stop signal (p.Glu357*) in the FAH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FAH are known to be pathogenic (PMID: 9101289, 9633815). This variant is present in population databases (rs121965075, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with tyrosinemia type I (PMID: 8318997). ClinVar contains an entry for this variant (Variation ID: 11871). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 03, 2016	Variant summary: The FAH c.1069G>T (p.Glu357X) variant results in a premature termination codon, predicted to cause a truncated or absent FAH protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 3/121286 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic FAH variant (0.0025). The variant has been reported in numerous affected indiivduals in the literature. In addition, one databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1993	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 26, 2018	The p.Glu357X variant in FAH has been reported in at least two compound heterozy gous individuals with Tyrosinemia type 1 (Grompe 1993, Kvittingen 1994, Ploos va n Amstel 1996). Sequencing of a patient mRNA showed a loss of expression of the transcript with this variant (Ploos van Amstel 1996). This variant has been iden tified in 9/129178 European chromosomes by the Genome Aggregation Database (gnom AD, http://gnomad.broadinstitute.org) and reported in ClinVar (Variation ID: 118 71). This nonsense variant leads to a premature termination codon at position 35 7, which is predicted to lead to a truncated or absent protein. Biallelic loss o f function of the FAH gene is an established disease mechanism in Tyrosinemia Ty pe 1. In summary, this variant meets criteria to be classified as pathogenic for Tyrosinemia Type 1 in an autosomal recessive manner based upon presence in affe cted individuals, low frequency in controls, and the predicted impact to the pro tein. ACMG/AMP criteria applied: PVS1, PM3_Strong, PM2, PS3_Supporting. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 16, 2022

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9633815, 8318997, 8557261, 7929843, 15638932, 22975760, 25525159, 7757089, 26689913, 27415407, 22554029, 29625052, 8076937) -

FAH-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 25, 2023

The FAH c.1069G>T variant is predicted to result in premature protein termination (p.Glu357*). This variant has been commonly reported as causative for tyrosinemia type I (Grompe et al. 1993. PubMed ID: 8318997; Angileri et al. 2015. PubMed ID: 25681080). This variant is reported in 0.0070% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-80473390-G-T). Nonsense variants 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

0.51

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.88

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.96

MutationTaster

Benign

1.0

A;A;A;A

Vest4

0.98

GERP RS

4.4

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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