15-80153057-G-A

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_000137.4(FAH):c.3G>A(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,134 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: 0.0000014 (0 hom.)
• Consequence: FAH NM_000137.4 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.01

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 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_000137.4 (FAH) was described as [Likely_pathogenic] in ClinVar as 371005
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-80153057-G-A is Pathogenic according to our data. Variant chr15-80153057-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 950962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAH	NM_000137.4	c.3G>A	p.Met1?	start_lost	1/14	ENST00000561421.6
FAH	NM_001374377.1	c.3G>A	p.Met1?	start_lost	2/15
FAH	NM_001374380.1	c.3G>A	p.Met1?	start_lost	2/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAH	ENST00000561421.6	c.3G>A	p.Met1?	start_lost	1/14	1	NM_000137.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250716 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135622

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: 0.00000137 AC: 2 AN: 1461134 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726926

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tyrosinemia type I Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 27, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 30, 2023	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 (rs766882348, 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: 950962). 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	Mar 02, 2023	Variant summary: FAH c.3G>A (p.Met1Ile) 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. Other variants that disrupt the initiator codon have been reported in association with Tyrosinaemia 1 in HGMD. 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 250716 control chromosomes. The next downstream in-frame initiation codon is at codon 71 and other pathogenic variants have been reported upstream of this potential in-frame start codon. c.3G>A has been reported in the literature as a homozygous genotype in individuals affected with Tyrosinemia Type 1 (Ibarra-Gonzalez_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.075	T;D;D;D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;.;.;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.48	D
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Uncertain	-2.9	D;D;D;D
Sift	Uncertain	0.012	D;D;D;D
Sift4G	Benign	0.090	T;T;T;T
Polyphen		0.93	.;P;P;P
Vest4		0.94, 0.83, 0.92
MutPred		0.97		Gain of catalytic residue at M1 (P = 0.0374);Gain of catalytic residue at M1 (P = 0.0374);Gain of catalytic residue at M1 (P = 0.0374);Gain of catalytic residue at M1 (P = 0.0374);
MVP		0.88
ClinPred		0.97	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.56

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

Other links and lift over

dbSNP: rs766882348; hg19: chr15-80445399;