15-80153055-A-C

Position:

• chr15-80153055-A-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000137.4(FAH):​c.1A>C​(p.Met1?) variant causes a start lost 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 start_lost
• 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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• 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/exons	MANE	Protein	UniProt
FAH	NM_000137.4	c.1A>C	p.Met1?	start_lost	1/14	ENST00000561421.6	NP_000128.1
FAH	NM_001374377.1	c.1A>C	p.Met1?	start_lost	2/15		NP_001361306.1
FAH	NM_001374380.1	c.1A>C	p.Met1?	start_lost	2/15		NP_001361309.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAH	ENST00000561421.6	c.1A>C	p.Met1?	start_lost	1/14	1	NM_000137.4	ENSP00000453347	P1

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 09, 2020

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. 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. 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. -

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
MutationTaster	Benign	1.0	D;D;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;