15-80159830-G-C

Variant names:

• chr15-80159830-G-C
• rs33929922
• NM_000137.4:c.267G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.56
• Publications: 8 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 -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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar as Benign. Clinvar id is 92444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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	c.267G>C	p.Leu89Leu	synonymous_variant	Exon 3 of 14	ENST00000561421.6	NP_000128.1
FAH	NM_001374377.1	c.267G>C	p.Leu89Leu	synonymous_variant	Exon 4 of 15		NP_001361306.1
FAH	NM_001374380.1	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	c.267G>C	p.Leu89Leu	synonymous_variant	Exon 3 of 14	1	NM_000137.4	ENSP00000453347.2

Frequencies

GnomAD3 genomes AF: 0.0745 AC: 11339 AN: 152196 Hom.: 429 Cov.: 34

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

GnomAD2 exomes AF: 0.0735 AC: 18492 AN: 251458 AF XY: 0.0738

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 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.: 41 AF XY: 0.0803 AC XY: 58421 AN XY: 727214

African (AFR) AF: 0.0759 AC: 2541 AN: 33480

American (AMR) AF: 0.0809 AC: 3617 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0607 AC: 1587 AN: 26136

East Asian (EAS) AF: 0.0295 AC: 1173 AN: 39700

South Asian (SAS) AF: 0.0888 AC: 7659 AN: 86258

European-Finnish (FIN) AF: 0.0538 AC: 2872 AN: 53418

Middle Eastern (MID) AF: 0.0702 AC: 405 AN: 5768

European-Non Finnish (NFE) AF: 0.0837 AC: 93036 AN: 1111954

Other (OTH) AF: 0.0742 AC: 4482 AN: 60392

GnomAD4 genome AF: 0.0745 AC: 11354 AN: 152314 Hom.: 431 Cov.: 34 AF XY: 0.0730 AC XY: 5434 AN XY: 74482

African (AFR) AF: 0.0766 AC: 3186 AN: 41580

American (AMR) AF: 0.0717 AC: 1098 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0576 AC: 200 AN: 3472

East Asian (EAS) AF: 0.0226 AC: 117 AN: 5188

South Asian (SAS) AF: 0.0877 AC: 424 AN: 4832

European-Finnish (FIN) AF: 0.0539 AC: 572 AN: 10604

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0805 AC: 5476 AN: 68012

Other (OTH) AF: 0.0620 AC: 131 AN: 2114

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

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

- -

Jun 10, 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. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:3

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. -

-

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

- -

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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. -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	3.3
DANN	Benign	0.51
PhyloP100		1.6
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: rs33929922; hg19: chr15-80452172; COSMIC: COSV55723013; COSMIC: COSV55723013;