NM_000137.4:c.1A>C

Variant names:

• chr15-80153055-A-C
• NM_000137.4:c.1A>C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000137.4(FAH):​c.1A>C​(p.Met1?) variant causes a initiator codon change involving the alteration of a 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FAH NM_000137.4 initiator_codon
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.47

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.

• 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-C is Pathogenic according to our data. Variant chr15-80153055-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1066042.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tyrosinemia type I Pathogenic:1

Jul 09, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. A different variant (c.1A>G) giving rise to the same protein effect observed here (p.Met1?) has been determined to be pathogenic (PMID: 21764616, 22802474, 24016420). This suggests that this variant is also likely to be causative of disease. This variant has not been reported in the literature in individuals with FAH-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the FAH mRNA. The next in-frame methionine is located at codon 71. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.029	T;T;T;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;.;.;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.19	D
PROVEAN	Benign	-2.0	N;N;N;N
REVEL	Pathogenic	0.74
Sift	Uncertain	0.023	D;T;T;T
Sift4G	Benign	0.19	T;T;T;T
Polyphen		0.84	.;P;P;P
Vest4		0.95, 0.73, 0.91
MutPred		0.98		Loss of disorder (P = 0.1523);Loss of disorder (P = 0.1523);Loss of disorder (P = 0.1523);Loss of disorder (P = 0.1523);
MVP		0.86
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.49

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-80445397;