chr15-80180219-C-T

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.1056C>T(p.Ser352Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0505 in 1,605,318 control chromosomes in the GnomAD database, including 2,444 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.054 ( 296 hom., cov: 32)

Exomes 𝑓: 0.050 ( 2148 hom. )

Consequence

FAH
NM_000137.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.693

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=-0.56).

BP6

Variant 15-80180219-C-T is Benign according to our data. Variant chr15-80180219-C-T is described in ClinVar as [Benign]. Clinvar id is 167054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-80180219-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.693 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0805 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAH	NM_000137.4 link	c.1056C>T	p.Ser352Ser	synonymous_variant	Exon 12 of 14	ENST00000561421.6	NP_000128.1	P16930-1A0A384P5L6
FAH	NM_001374377.1 link	c.1056C>T	p.Ser352Ser	synonymous_variant	Exon 13 of 15		NP_001361306.1
FAH	NM_001374380.1 link	c.1056C>T	p.Ser352Ser	synonymous_variant	Exon 13 of 15		NP_001361309.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAH	ENST00000561421.6 link	c.1056C>T	p.Ser352Ser	synonymous_variant	Exon 12 of 14	1	NM_000137.4	ENSP00000453347.2		P16930-1

Frequencies

GnomAD3 genomes

AF:

0.0538

AC:

8179

AN:

152118

Hom.:

295

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0360

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.0699

Gnomad ASJ

AF:

0.0230

Gnomad EAS

AF:

0.0881

Gnomad SAS

AF:

0.0582

Gnomad FIN

AF:

0.114

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0501

Gnomad OTH

AF:

0.0713

GnomAD3 exomes

AF:

0.0573

AC:

13961

AN:

243748

Hom.:

482

AF XY:

0.0570

AC XY:

7558

AN XY:

132484

show subpopulations

Gnomad AFR exome

AF:

0.0355

Gnomad AMR exome

AF:

0.0698

Gnomad ASJ exome

AF:

0.0235

Gnomad EAS exome

AF:

0.0884

Gnomad SAS exome

AF:

0.0550

Gnomad FIN exome

AF:

0.104

Gnomad NFE exome

AF:

0.0482

Gnomad OTH exome

AF:

0.0673

GnomAD4 exome

AF:

0.0501

AC:

72854

AN:

1453082

Hom.:

2148

Cov.:

AF XY:

0.0504

AC XY:

36480

AN XY:

723236

show subpopulations

Gnomad4 AFR exome

AF:

0.0370

Gnomad4 AMR exome

AF:

0.0711

Gnomad4 ASJ exome

AF:

0.0231

Gnomad4 EAS exome

AF:

0.0791

Gnomad4 SAS exome

AF:

0.0537

Gnomad4 FIN exome

AF:

0.0968

Gnomad4 NFE exome

AF:

0.0469

Gnomad4 OTH exome

AF:

0.0506

GnomAD4 genome

AF:

0.0537

AC:

8179

AN:

152236

Hom.:

296

Cov.:

AF XY:

0.0576

AC XY:

4284

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.0360

Gnomad4 AMR

AF:

0.0700

Gnomad4 ASJ

AF:

0.0230

Gnomad4 EAS

AF:

0.0871

Gnomad4 SAS

AF:

0.0595

Gnomad4 FIN

AF:

0.114

Gnomad4 NFE

AF:

0.0500

Gnomad4 OTH

AF:

0.0701

Alfa

AF:

0.0402

Hom.:

Bravo

AF:

0.0486

Asia WGS

AF:

0.0920

AC:

318

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 19, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 22, 2016

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. -

Feb 01, 2018

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FAH c.1056C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.058 in 269822 control chromosomes in the gnomAD database, including 572 homozygotes. The observed variant frequency is over 20 fold of the estimated maximal expected allele frequency for a pathogenic variant in FAH causing Tyrosinemia Type 1 phenotype (0.0025), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1056C>T in individuals affected with Tyrosinemia Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Tyrosinemia type I

Benign:3

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

not provided

Benign:1

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

-0.56

CADD

Benign

3.9

DANN

Benign

0.59

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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