rs533540262

chr15-80172238-C-Achr15-80172238-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000137.4(FAH):c.696C>A(p.Asn232Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. N232N) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FAH NM_000137.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.0390

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000137.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAH	NM_000137.4	c.696C>A	p.Asn232Lys	missense_variant	8/14	ENST00000561421.6
FAH	NM_001374377.1	c.696C>A	p.Asn232Lys	missense_variant	9/15
FAH	NM_001374380.1	c.696C>A	p.Asn232Lys	missense_variant	9/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAH	ENST00000561421.6	c.696C>A	p.Asn232Lys	missense_variant	8/14	1	NM_000137.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251450 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135904

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1458110 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 725666

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 21, 2014

- -

Tyrosinemia type I Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

3billion

Sep 01, 2022

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.84; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with FAH-related disorder (PMID: 23430822). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D;D;D
Eigen	Benign	0.090
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.8	H;H;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.9	D;D;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.99
MutPred		0.92		Gain of MoRF binding (P = 0.073);Gain of MoRF binding (P = 0.073);Gain of MoRF binding (P = 0.073);
MVP		0.93
MPC		0.90
ClinPred		1.0	D
GERP RS		-1.6
Varity_R		0.97
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.28		Position offset: 10

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

Publications

LitVar

Other links and lift over

dbSNP: rs533540262; hg19: chr15-80464580;