15-80158170-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000137.4(FAH):c.192G>T(p.Gln64His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000405 in 1,606,282 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin Lovd.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

FAH
NM_000137.4 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11O:1

Conservation

PhyloP100: 8.76

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 14 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 15-80158170-G-T is Pathogenic according to our data. Variant chr15-80158170-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-80158170-G-T is described in Lovd as [Likely_pathogenic]. Variant chr15-80158170-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
FAH	NM_000137.4 linkuse as main transcript	c.192G>T	p.Gln64His	missense_variant, splice_region_variant	2/14	ENST00000561421.6
FAH	NM_001374377.1 linkuse as main transcript	c.192G>T	p.Gln64His	missense_variant, splice_region_variant	3/15
FAH	NM_001374380.1 linkuse as main transcript	c.192G>T	p.Gln64His	missense_variant, splice_region_variant	3/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAH	ENST00000561421.6 linkuse as main transcript	c.192G>T	p.Gln64His	missense_variant, splice_region_variant	2/14	1	NM_000137.4	P1	P16930-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152206

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000636

AC:

AN:

251492

Hom.:

AF XY:

0.0000809

AC XY:

AN XY:

135920

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:

0.000523

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000433

AC:

AN:

1454076

Hom.:

Cov.:

AF XY:

0.0000622

AC XY:

AN XY:

723908

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:

0.000697

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000333

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74356

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:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000844

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000659

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tyrosinemia type I

Pathogenic:9Other:1

not provided, no classification provided	literature only	GeneReviews	-	Pakistani-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	Jul 17, 2017	Variant summary: The FAH c.192G>T (p.Gln64His) variant involves the alteration of a conserved nucleotide. This variant defies the donor-splice-site consensus sequence and it is considered a splice-site mutation (Ijaz_JPEM_2015). Human 2/3 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). 5/5 splice prediction tools predict a significant impact on normal splicing. ESE finder predicts the loss of the SF2/ASF binding motif and the creation of a splice donor site. Functional studies showed decreased or absent FAH mRNA and protein levels in HT1 patients with this variant The variant of interest has been found in a large, broad control population, ExAC in 8/121410 control chromosomes at a frequency of 0.0000659, which does not exceed the estimated maximal expected allele frequency of a pathogenic FAH variant (0.0025). This variant has been reported in multiple HT1 patients, in both homozygotes and heterozygotes (with unknown secondary allele)( Rootwelt_AJHG_1994, Rootwelt_HM_1996, Ijaz_JPEM_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant c.192G>T(p.Gln64His) in FAH gene has been observed in individual(s) with tyrosinemia type I (Rootwelt H et.al.,1994). The amino acid Gln at position 64 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. This variant has been reported to the ClinVar database as Pathogenic. The p.Gln64His variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.006009% is reported in gnomAD. The variant is predicted to be damaging by SIFT and the residue is conserved across species. The amino acid change p.Gln64His in FAH is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic . -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000021054, PS1_S). Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product(PMID: 8829657, 7942842) (PS3_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (SPLICEAI: 0.9>=0.8, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000060, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 02, 2024	This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 64 of the FAH protein (p.Gln64His). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs80338894, gnomAD 0.05%). This missense change has been observed in individual(s) with tyrosinemia type I (PMID: 7942842; Invitae). ClinVar contains an entry for this variant (Variation ID: 21054). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in retention of 94 nucleotides of intron 2 and introduces a premature termination codon (PMID: 7942842). 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	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 09, 2019	NM_000137.2(FAH):c.192G>T(Q64H) is classified as pathogenic in the context of tyrosinemia type I. Sources cited for classification include the following: PMID 22975760, 23430822, 23193487, 14691918, 9101289 and 7942842. Classification of NM_000137.2(FAH):c.192G>T(Q64H) 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. -

T-substance anomaly

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Nov 22, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.090

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.69

D;D;D;D

Eigen

Benign

0.16

Eigen_PC

Benign

0.22

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

D;.;.;D

M_CAP

Uncertain

0.14

MetaRNN

Uncertain

0.46

T;T;T;T

MetaSVM

Uncertain

0.37

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-3.0

D;D;D;D

Sift

Uncertain

0.016

D;D;D;D

Sift4G

Uncertain

0.039

D;D;D;D

Polyphen

0.0060

.;B;B;B

Vest4

0.31, 0.31, 0.31

MutPred

0.51

Gain of disorder (P = 0.1404);Gain of disorder (P = 0.1404);Gain of disorder (P = 0.1404);Gain of disorder (P = 0.1404);

MVP

0.92

MPC

0.22

ClinPred

0.47

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.52

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.90

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.90

Position offset: 0

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