chr15-80152992-C-A

Variant names:

• chr15-80152992-C-A
• rs532122242
• ENST00000960162.1:c.-63C>A

Variant summary

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

The NM_001374377.1(FAH):​c.-29-34C>A variant causes a intron 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 NM_001374377.1 intron
• 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: Ambry Genetics, Myriad Women’s Health, G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Laboratory for Molecular Medicine

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

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.-29-34C>A		intron	N/A	NP_001361306.1	A0A384P5L6
	FAH	NM_001374380.1		c.-29-34C>A		intron	N/A	NP_001361309.1	A0A384P5L6
	FAH	NM_000137.4	MANE Select	c.-63C>A		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.-63C>A		5_prime_UTR	Exon 1 of 14	ENSP00000630221.1
	FAH	ENST00000929199.1		c.-63C>A		5_prime_UTR	Exon 1 of 14	ENSP00000599258.1
	FAH	ENST00000874658.1		c.-63C>A		5_prime_UTR	Exon 1 of 13	ENSP00000544717.1

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

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Tyrosinemia type I (1)

Computational scores

Source: dbNSFP v4.9

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;