15-80152992-C-A

Variant names:

• chr15-80152992-C-A
• rs532122242
• ENST00000682012.1:n.13C>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000682012.1(FAH):​n.13C>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,467,034 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00088 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (2 hom.)
• Consequence: FAH ENST00000682012.1 non_coding_transcript_exon
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.914
• Publications: 0 publications found

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]

FAH Gene-Disease associations (from GenCC):

• tyrosinemia type I

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Laboratory for Molecular Medicine, G2P, Orphanet, Ambry Genetics, ClinGen

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAH	NM_001374377.1	c.-29-34C>A		intron_variant	Intron 1 of 14		NP_001361306.1
FAH	NM_001374380.1	c.-29-34C>A		intron_variant	Intron 1 of 14		NP_001361309.1
FAH	NM_000137.4	c.-63C>A		upstream_gene_variant		ENST00000561421.6	NP_000128.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAH	ENST00000561421.6	c.-63C>A		upstream_gene_variant		1	NM_000137.4	ENSP00000453347.2

Frequencies

GnomAD3 genomes AF: 0.000881 AC: 134 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00157

Gnomad OTH AF: 0.00144

GnomAD4 exome AF: 0.00127 AC: 1676 AN: 1314754 Hom.: 2 Cov.: 20 AF XY: 0.00124 AC XY: 821 AN XY: 662070

African (AFR) AF: 0.0000325 AC: 1 AN: 30796

American (AMR) AF: 0.000899 AC: 40 AN: 44492

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25256

East Asian (EAS) AF: 0.00 AC: 0 AN: 38994

South Asian (SAS) AF: 0.000431 AC: 36 AN: 83548

European-Finnish (FIN) AF: 0.000460 AC: 20 AN: 43514

Middle Eastern (MID) AF: 0.000182 AC: 1 AN: 5498

European-Non Finnish (NFE) AF: 0.00155 AC: 1527 AN: 986896

Other (OTH) AF: 0.000915 AC: 51 AN: 55760

GnomAD4 genome AF: 0.000880 AC: 134 AN: 152280 Hom.: 0 Cov.: 33 AF XY: 0.000846 AC XY: 63 AN XY: 74448

African (AFR) AF: 0.000192 AC: 8 AN: 41582

American (AMR) AF: 0.000719 AC: 11 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00157 AC: 107 AN: 68000

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000212 Hom.: 0

Bravo AF: 0.000876

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tyrosinemia type I Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.2
DANN	Benign	0.60
PhyloP100		-0.91
PromoterAI		-0.13	Neutral
Mutation Taster		=272/28	polymorphism

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

Other links and lift over

dbSNP: rs532122242; hg19: chr15-80445334;