rs1370275

Variant names:

• chr15-80158047-G-A
• rs1370275
• ENST00000539156.5:n.2097G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000539156.5(FAH):​n.2097G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.512 in 1,604,670 control chromosomes in the GnomAD database, including 215,209 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (17032 hom., cov: 31)
  • Exomes 𝑓: 0.52 (198177 hom.)
• Consequence: FAH ENST00000539156.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -4.70
• Publications: 12 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: Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Laboratory for Molecular Medicine, G2P, Orphanet, Ambry Genetics, ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.04).
• BP6: Variant 15-80158047-G-A is Benign according to our data. Variant chr15-80158047-G-A is described in ClinVar as Benign. ClinVar VariationId is 92446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.739 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAH	NM_000137.4	c.82-13G>A		intron_variant	Intron 1 of 13	ENST00000561421.6	NP_000128.1
FAH	NM_001374377.1	c.82-13G>A		intron_variant	Intron 2 of 14		NP_001361306.1
FAH	NM_001374380.1	c.82-13G>A		intron_variant	Intron 2 of 14		NP_001361309.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAH	ENST00000561421.6	c.82-13G>A		intron_variant	Intron 1 of 13	1	NM_000137.4	ENSP00000453347.2

Frequencies

GnomAD3 genomes AF: 0.461 AC: 69992 AN: 151768 Hom.: 17037 Cov.: 31

Gnomad AFR AF: 0.318

Gnomad AMI AF: 0.515

Gnomad AMR AF: 0.439

Gnomad ASJ AF: 0.548

Gnomad EAS AF: 0.758

Gnomad SAS AF: 0.590

Gnomad FIN AF: 0.450

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.517

Gnomad OTH AF: 0.492

GnomAD2 exomes AF: 0.511 AC: 128519 AN: 251430 AF XY: 0.522

Gnomad AFR exome AF: 0.312

Gnomad AMR exome AF: 0.390

Gnomad ASJ exome AF: 0.553

Gnomad EAS exome AF: 0.762

Gnomad FIN exome AF: 0.458

Gnomad NFE exome AF: 0.516

Gnomad OTH exome AF: 0.498

GnomAD4 exome AF: 0.517 AC: 751629 AN: 1452784 Hom.: 198177 Cov.: 30 AF XY: 0.521 AC XY: 376826 AN XY: 723388

African (AFR) AF: 0.301 AC: 10009 AN: 33272

American (AMR) AF: 0.397 AC: 17759 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.550 AC: 14338 AN: 26092

East Asian (EAS) AF: 0.769 AC: 30482 AN: 39658

South Asian (SAS) AF: 0.609 AC: 52441 AN: 86088

European-Finnish (FIN) AF: 0.463 AC: 24740 AN: 53410

Middle Eastern (MID) AF: 0.579 AC: 3293 AN: 5686

European-Non Finnish (NFE) AF: 0.514 AC: 567030 AN: 1103776

Other (OTH) AF: 0.525 AC: 31537 AN: 60090

GnomAD4 genome AF: 0.461 AC: 70017 AN: 151886 Hom.: 17032 Cov.: 31 AF XY: 0.461 AC XY: 34185 AN XY: 74222

African (AFR) AF: 0.318 AC: 13171 AN: 41432

American (AMR) AF: 0.438 AC: 6686 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.548 AC: 1901 AN: 3470

East Asian (EAS) AF: 0.759 AC: 3901 AN: 5142

South Asian (SAS) AF: 0.589 AC: 2836 AN: 4812

European-Finnish (FIN) AF: 0.450 AC: 4744 AN: 10532

Middle Eastern (MID) AF: 0.592 AC: 174 AN: 294

European-Non Finnish (NFE) AF: 0.517 AC: 35100 AN: 67930

Other (OTH) AF: 0.491 AC: 1036 AN: 2112

Alfa AF: 0.508 Hom.: 62893

Bravo AF: 0.449

Asia WGS AF: 0.606 AC: 2106 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tyrosinemia type I Benign:5

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 26, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Benign:4

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 25, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.0030
DANN	Benign	0.27
PhyloP100		-4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs1370275; hg19: chr15-80450389;