15-80152877-G-A

Variant summary

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

The NM_001374377.1(FAH):c.-58G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4292 hom., cov: 19)
  • Exomes 𝑓: 0.27 (17354 hom.)
• Consequence: FAH NM_001374377.1 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.908

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=-0.8).
• BP6: Variant 15-80152877-G-A is Benign according to our data. Variant chr15-80152877-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 369102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.292 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAH	NM_001374377.1	c.-58G>A		5_prime_UTR_variant	1/15
FAH	NM_001374380.1	c.-30+36G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAH	ENST00000407106.5	c.-58G>A		5_prime_UTR_variant	1/15	5		P1
FAH	ENST00000558767.6	c.-178G>A		5_prime_UTR_variant	1/5	2
FAH	ENST00000261755.9	c.-30+36G>A		intron_variant		5		P1

Frequencies

GnomAD3 genomes AF: 0.225 AC: 32102 AN: 142456 Hom.: 4297 Cov.: 19

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.447

Gnomad AMR AF: 0.218

Gnomad ASJ AF: 0.248

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.207

Gnomad FIN AF: 0.268

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.296

Gnomad OTH AF: 0.228

GnomAD4 exome AF: 0.269 AC: 123429 AN: 459126 Hom.: 17354 Cov.: 4 AF XY: 0.267 AC XY: 64912 AN XY: 242774

Gnomad4 AFR exome AF: 0.116

Gnomad4 AMR exome AF: 0.218

Gnomad4 ASJ exome AF: 0.259

Gnomad4 EAS exome AF: 0.157

Gnomad4 SAS exome AF: 0.229

Gnomad4 FIN exome AF: 0.286

Gnomad4 NFE exome AF: 0.300

Gnomad4 OTH exome AF: 0.262

GnomAD4 genome AF: 0.225 AC: 32114 AN: 142558 Hom.: 4292 Cov.: 19 AF XY: 0.223 AC XY: 15412 AN XY: 69066

Gnomad4 AFR AF: 0.105

Gnomad4 AMR AF: 0.218

Gnomad4 ASJ AF: 0.248

Gnomad4 EAS AF: 0.136

Gnomad4 SAS AF: 0.208

Gnomad4 FIN AF: 0.268

Gnomad4 NFE AF: 0.296

Gnomad4 OTH AF: 0.226

Alfa AF: 0.272 Hom.: 817

Bravo AF: 0.221

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 29, 2018

- -

Hypertyrosinemia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Tyrosinemia type I Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Jul 26, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	7.2
Dann	Benign	0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs56043846; hg19: chr15-80445219; COSMIC: COSV55722092; COSMIC: COSV55722092;