Genetic Variant FAH:p.Met1? (chr15-80153055-A-G) – ACMG Classification: Pathogenic (14 pts)

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_000137.4(FAH):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,136 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 (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

FAH
NM_000137.4 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 7.47

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 6 pathogenic variants. Next in-frame start position is after 71 codons. Genomic position: 80159774. Lost 0.167 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 15-80153055-A-G is Pathogenic according to our data. Variant chr15-80153055-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 372766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAH	NM_000137.4 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 14	ENST00000561421.6	NP_000128.1	P16930-1A0A384P5L6
FAH	NM_001374377.1 link	c.1A>G	p.Met1?	start_lost	Exon 2 of 15		NP_001361306.1
FAH	NM_001374380.1 link	c.1A>G	p.Met1?	start_lost	Exon 2 of 15		NP_001361309.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAH	ENST00000561421.6 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 14	1	NM_000137.4	ENSP00000453347.2		P16930-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000798

AC:

AN:

250698

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135612

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461136

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726924

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000450

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tyrosinemia type I

Pathogenic:7

Jun 17, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the FAH mRNA. The next in-frame methionine is located at codon 71. This variant is present in population databases (no rsID available, gnomAD 0.003%). Disruption of the initiator codon has been observed in individual(s) with tyrosinemia type I (PMID: 21764616, 22802474, 24016420). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372766). For these reasons, this variant has been classified as Pathogenic. -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 21, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FAH c.1A>G (p.Met1Val) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Three of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250698 control chromosomes (gnomAD). c.1A>G has been reported in the literature in multiple individuals (several of them were homozygous) affected with Tyrosinemia Type 1 (example: Ibarra-Gonzalez_2019, Mohamed_2013, Imtiaz_2011). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Macias_2019). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Dec 19, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 06, 2014

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Pathogenic:2

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FAH: PM2, PM3, PM5, PP4:Moderate, PVS1:Moderate -

Dec 13, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Initiation codon variant 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: 24016420, 24516753, 34426522, 31568711, 31300554) -

See cases

Pathogenic:1

Feb 28, 2023

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PVS1,PM2,PP5 -

Tyrosinemia

Pathogenic:1

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PVS1,PP1,PM2,PM3,PM5,PP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.37

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.078

T;T;T;T

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.90

D;.;.;D

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Uncertain

-0.048

PROVEAN

Uncertain

-2.5

D;N;N;N

REVEL

Pathogenic

0.69

Sift

Benign

0.15

T;T;T;T

Sift4G

Benign

0.22

T;T;T;T

Polyphen

0.26

.;B;B;B

Vest4

0.98, 0.82, 0.95

MutPred

0.99

Loss of disorder (P = 0.1857);Loss of disorder (P = 0.1857);Loss of disorder (P = 0.1857);Loss of disorder (P = 0.1857);

MVP

0.84

ClinPred

0.97

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.70

gMVP

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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