chr15-80152896-C-A

Variant names:

• chr15-80152896-C-A
• rs2041062775
• ENST00000561369.1:n.42C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000561369.1(FAH):​n.42C>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 0.00000202 in 494,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000020 (0 hom.)
• Consequence: FAH ENST00000561369.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.68
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAH	NM_001374377.1	c.-39C>A		5_prime_UTR_variant	Exon 1 of 15		NP_001361306.1
FAH	NM_001374380.1	c.-30+55C>A		intron_variant	Intron 1 of 14		NP_001361309.1
FAH	NM_000137.4	c.-159C>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.-159C>A		upstream_gene_variant		1	NM_000137.4	ENSP00000453347.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000202 AC: 1 AN: 494896 Hom.: 0 Cov.: 6 AF XY: 0.00 AC XY: 0 AN XY: 262714

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 14354

American (AMR) AF: 0.00 AC: 0 AN: 27654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15282

East Asian (EAS) AF: 0.00 AC: 0 AN: 30898

South Asian (SAS) AF: 0.00 AC: 0 AN: 52192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30042

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2132

European-Non Finnish (NFE) AF: 0.00000339 AC: 1 AN: 294652

Other (OTH) AF: 0.00 AC: 0 AN: 27690

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.1
DANN	Benign	0.62
PhyloP100		-1.7
PromoterAI		0.0046	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2041062775; hg19: chr15-80445238;