15-80152988-C-T

Variant names:

• chr15-80152988-C-T
• rs886051495
• ENST00000960162.1:c.-67C>T

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.-29-38C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FAH NM_001374377.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.225
• 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics, Myriad Women’s Health, 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=-0.78).

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.-29-38C>T		intron	N/A	NP_001361306.1	A0A384P5L6
	FAH	NM_001374380.1		c.-29-38C>T		intron	N/A	NP_001361309.1	A0A384P5L6
	FAH	NM_000137.4	MANE Select	c.-67C>T		upstream_gene	N/A	NP_000128.1	A0A384P5L6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAH	ENST00000960162.1		c.-67C>T		5_prime_UTR	Exon 1 of 14	ENSP00000630221.1
	FAH	ENST00000929199.1		c.-67C>T		5_prime_UTR	Exon 1 of 14	ENSP00000599258.1
	FAH	ENST00000874658.1		c.-67C>T		5_prime_UTR	Exon 1 of 13	ENSP00000544717.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1278492 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 645534

African (AFR) AF: 0.00 AC: 0 AN: 30100

American (AMR) AF: 0.00 AC: 0 AN: 44374

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25002

East Asian (EAS) AF: 0.00 AC: 0 AN: 38798

South Asian (SAS) AF: 0.00 AC: 0 AN: 82832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5414

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 954860

Other (OTH) AF: 0.00 AC: 0 AN: 54522

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	3.9
DANN	Benign	0.76
PhyloP100		0.23
PromoterAI		-0.16	Neutral

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: rs886051495; hg19: chr15-80445330;