chr15-80152950-G-C

Position:

• chr15-80152950-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000558767.6(FAH):​c.-105G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 975,720 control chromosomes in the GnomAD database, including 37,728 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4547 hom., cov: 28)
  • Exomes 𝑓: 0.28 (33181 hom.)
• Consequence: FAH ENST00000558767.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.77

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 15-80152950-G-C is Benign according to our data. Variant chr15-80152950-G-C is described in ClinVar as [Benign]. Clinvar id is 317196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-80152950-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.296 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAH	NM_001374377.1	c.-30+45G>C		intron_variant
FAH	NM_001374380.1	c.-29-76G>C		intron_variant
FAH	NM_000137.4			upstream_gene_variant		ENST00000561421.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAH	ENST00000561421.6			upstream_gene_variant		1	NM_000137.4	P1

Frequencies

GnomAD3 genomes AF: 0.232 AC: 34686 AN: 149758 Hom.: 4553 Cov.: 28

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.458

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.248

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.287

Gnomad MID AF: 0.172

Gnomad NFE AF: 0.300

Gnomad OTH AF: 0.235

GnomAD4 exome AF: 0.279 AC: 230060 AN: 825848 Hom.: 33181 Cov.: 11 AF XY: 0.278 AC XY: 119872 AN XY: 431872

Gnomad4 AFR exome AF: 0.117

Gnomad4 AMR exome AF: 0.215

Gnomad4 ASJ exome AF: 0.258

Gnomad4 EAS exome AF: 0.157

Gnomad4 SAS exome AF: 0.232

Gnomad4 FIN exome AF: 0.285

Gnomad4 NFE exome AF: 0.304

Gnomad4 OTH exome AF: 0.263

GnomAD4 genome AF: 0.232 AC: 34698 AN: 149872 Hom.: 4547 Cov.: 28 AF XY: 0.230 AC XY: 16846 AN XY: 73120

Gnomad4 AFR AF: 0.114

Gnomad4 AMR AF: 0.226

Gnomad4 ASJ AF: 0.248

Gnomad4 EAS AF: 0.136

Gnomad4 SAS AF: 0.223

Gnomad4 FIN AF: 0.287

Gnomad4 NFE AF: 0.300

Gnomad4 OTH AF: 0.234

Alfa AF: 0.271 Hom.: 700

Bravo AF: 0.220

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tyrosinemia type I Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 26, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.3
DANN	Benign	0.53

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

Publications

LitVar

Other links and lift over

dbSNP: rs112474268; hg19: chr15-80445292;