NM_000137.4:c.267G>C

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000137.4(FAH):c.267G>C(p.Leu89Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0797 in 1,614,142 control chromosomes in the GnomAD database, including 5,166 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.075 ( 431 hom., cov: 34)

Exomes 𝑓: 0.080 ( 4735 hom. )

Consequence

FAH
NM_000137.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.56

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 15-80159830-G-C is Benign according to our data. Variant chr15-80159830-G-C is described in ClinVar as [Benign]. Clinvar id is 92444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-80159830-G-C is described in Lovd as [Benign]. Variant chr15-80159830-G-C is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=1.56 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0809 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAH	NM_000137.4 link	c.267G>C	p.Leu89Leu	synonymous_variant	Exon 3 of 14	ENST00000561421.6	NP_000128.1	P16930-1A0A384P5L6
FAH	NM_001374377.1 link	c.267G>C	p.Leu89Leu	synonymous_variant	Exon 4 of 15		NP_001361306.1
FAH	NM_001374380.1 link	c.267G>C	p.Leu89Leu	synonymous_variant	Exon 4 of 15		NP_001361309.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAH	ENST00000561421.6 link	c.267G>C	p.Leu89Leu	synonymous_variant	Exon 3 of 14	1	NM_000137.4	ENSP00000453347.2		P16930-1

Frequencies

GnomAD3 genomes

AF:

0.0745

AC:

11339

AN:

152196

Hom.:

429

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0764

Gnomad AMI

AF:

0.139

Gnomad AMR

AF:

0.0718

Gnomad ASJ

AF:

0.0576

Gnomad EAS

AF:

0.0223

Gnomad SAS

AF:

0.0881

Gnomad FIN

AF:

0.0539

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0805

Gnomad OTH

AF:

0.0626

GnomAD3 exomes

AF:

0.0735

AC:

18492

AN:

251458

Hom.:

690

AF XY:

0.0738

AC XY:

10033

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.0764

Gnomad AMR exome

AF:

0.0847

Gnomad ASJ exome

AF:

0.0614

Gnomad EAS exome

AF:

0.0231

Gnomad SAS exome

AF:

0.0838

Gnomad FIN exome

AF:

0.0541

Gnomad NFE exome

AF:

0.0799

Gnomad OTH exome

AF:

0.0728

GnomAD4 exome

AF:

0.0803

AC:

117372

AN:

1461828

Hom.:

4735

Cov.:

AF XY:

0.0803

AC XY:

58421

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.0759

Gnomad4 AMR exome

AF:

0.0809

Gnomad4 ASJ exome

AF:

0.0607

Gnomad4 EAS exome

AF:

0.0295

Gnomad4 SAS exome

AF:

0.0888

Gnomad4 FIN exome

AF:

0.0538

Gnomad4 NFE exome

AF:

0.0837

Gnomad4 OTH exome

AF:

0.0742

GnomAD4 genome

AF:

0.0745

AC:

11354

AN:

152314

Hom.:

431

Cov.:

AF XY:

0.0730

AC XY:

5434

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.0766

Gnomad4 AMR

AF:

0.0717

Gnomad4 ASJ

AF:

0.0576

Gnomad4 EAS

AF:

0.0226

Gnomad4 SAS

AF:

0.0877

Gnomad4 FIN

AF:

0.0539

Gnomad4 NFE

AF:

0.0805

Gnomad4 OTH

AF:

0.0620

Alfa

AF:

0.0763

Hom.:

152

Bravo

AF:

0.0764

Asia WGS

AF:

0.0510

AC:

177

AN:

3478

EpiCase

AF:

0.0794

EpiControl

AF:

0.0795

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tyrosinemia type I

Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 04, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 15, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The FAH c.267G>C (p.Leu89Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. Mutation Taster predicts the variant to be a polymorphism. 5/5 splice prediction tools predict no significant impact on normal splicing, however no functional studies were published at the time of evaluation. This variant was found in 9078/121340 control chromosomes (including 353 homozygotes) at a frequency of 0.0748146, which is approximately 30 times the estimated maximal expected allele frequency of a pathogenic FAH variant (0.0025), suggesting this variant is likely a benign common polymorphism. In addition, one clinical diagnostic laboratory has classified this variant as benign. Taken together, this variant is classified as Benign. -

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

-0.64

CADD

Benign

3.3

DANN

Benign

0.51

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over