rs2041062775

Variant names:

• chr15-80152896-C-A
• rs2041062775
• ENST00000874657.1:c.-39C>A

Your query was ambiguous. Multiple possible variants found:

• chr15-80152896-C-A
• chr15-80152896-C-G

Variant summary

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

The NM_001374377.1(FAH):​c.-39C>A variant causes a 5 prime UTR 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 NM_001374377.1 5_prime_UTR
• 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: Ambry Genetics, Myriad Women’s Health, G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Laboratory for Molecular Medicine

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).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374377.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAH	NM_001374377.1		c.-39C>A		5_prime_UTR	Exon 1 of 15	NP_001361306.1	A0A384P5L6
	FAH	NM_001374380.1		c.-30+55C>A		intron	N/A	NP_001361309.1	A0A384P5L6
	FAH	NM_000137.4	MANE Select	c.-159C>A		upstream_gene	N/A	NP_000128.1	A0A384P5L6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAH	ENST00000874657.1		c.-39C>A		5_prime_UTR	Exon 1 of 16	ENSP00000544716.1
	FAH	ENST00000407106.5	TSL:5	c.-39C>A		5_prime_UTR	Exon 1 of 15	ENSP00000385080.1	P16930-1
	FAH	ENST00000874652.1		c.-64C>A		5_prime_UTR	Exon 1 of 15	ENSP00000544711.1

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), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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;