rs80338900

chr15-80180172-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP3 PP5_Very_Strong

The NM_000137.4(FAH):c.1009G>A(p.Gly337Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000534 in 1,610,718 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000054 (0 hom.)
• Consequence: FAH NM_000137.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 9.13

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 13 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000137.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 15-80180172-G-A is Pathogenic according to our data. Variant chr15-80180172-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-80180172-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAH	NM_000137.4	c.1009G>A	p.Gly337Ser	missense_variant	12/14	ENST00000561421.6
FAH	NM_001374377.1	c.1009G>A	p.Gly337Ser	missense_variant	13/15
FAH	NM_001374380.1	c.1009G>A	p.Gly337Ser	missense_variant	13/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAH	ENST00000561421.6	c.1009G>A	p.Gly337Ser	missense_variant	12/14	1	NM_000137.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

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: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000724 AC: 18 AN: 248584 Hom.: 0 AF XY: 0.0000594 AC XY: 8 AN XY: 134682

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000209

Gnomad NFE exome AF: 0.0000793

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000542 AC: 79 AN: 1458562 Hom.: 0 Cov.: 32 AF XY: 0.0000482 AC XY: 35 AN XY: 725760

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000120

Gnomad4 NFE exome AF: 0.0000603

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74318

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000591 Hom.: 0

Bravo AF: 0.0000642

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000115 AC: 14

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tyrosinemia type I Pathogenic:8 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 23, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 21, 2020	Variant summary: FAH c.1009G>A (p.Gly337Ser) results in a non-conservative amino acid change located in the C-terminal domain (IPR011234) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. In addition, several computational tools predict a significant impact on normal splicing: Three predict the variant creates a 3 acceptor site. This prediction has been confirmed by a study, using fibroblast derived mRNA from a homozygous patient, which has demonstrated the variant creates a functional acceptor splice site within exon 12, resulting in aberrant splice products (Rootwelt_1994). The variant had an incomplete effect on splicing, as the full length product, coding for the missense protein, was also detected in comparable amounts to the aberrant splice products (Rootwelt_1994). Though in this study no immunoreactive FAH protein could be detected in patient fibroblasts (Rootwelt_1994), the authors later noted that the resulting protein with G337S has about 19-31 % of normal FAH activity (Rootwelt_1996). The variant allele was found at a frequency of 7.2e-05 in 248584 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in FAH causing Tyrosinemia Type 1 (7.2e-05 vs 0.0025), allowing no conclusion about variant significance. c.1009G>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Tyrosinemia Type 1 (example: Rootwelt_1994, Rootwelt 1996, Haghighi-Kakhki_2014). These data indicate that the variant is very likely to be associated with disease. One other ClinVar submitter (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	Scandinavian population-specific pathogenic variant resulting from founder effect or genetic drift [Angileri et al 2015]. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 13, 2024	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 337 of the FAH protein (p.Gly337Ser). 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 (rs80338900, gnomAD 0.02%). This missense change has been observed in individual(s) with tyrosinemia type 1 (PMID: 8076937, 9633815, 22554029, 24756054). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 11869). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FAH protein function with a positive predictive value of 80%. Studies have shown that this missense change results in removing the first 50 nucleotides of exon 12 and introduces a premature termination codon (PMID: 24756054). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 23, 2021	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Dec 24, 2014	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 1995	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	35
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;D;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;M;M
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.6	D;D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.95
MVP		0.93
MPC		0.84
ClinPred		0.97	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.61		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.61		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80338900; hg19: chr15-80472514; COSMIC: COSV105066275;