chr15-80180219-C-T

Variant names:

• chr15-80180219-C-T
• rs1801374
• NM_000137.4:c.1056C>T

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.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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.693
• Publications: 9 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=-0.56).
• BP6: Variant 15-80180219-C-T is Benign according to our data. Variant chr15-80180219-C-T is described in ClinVar as Benign. ClinVar VariationId is 167054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000137.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAH	NM_000137.4	MANE Select	c.1056C>T	p.Ser352Ser	synonymous	Exon 12 of 14	NP_000128.1
	FAH	NM_001374377.1		c.1056C>T	p.Ser352Ser	synonymous	Exon 13 of 15	NP_001361306.1
	FAH	NM_001374380.1		c.1056C>T	p.Ser352Ser	synonymous	Exon 13 of 15	NP_001361309.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAH	ENST00000561421.6	TSL:1 MANE Select	c.1056C>T	p.Ser352Ser	synonymous	Exon 12 of 14	ENSP00000453347.2
	FAH	ENST00000539156.5	TSL:1	n.3084C>T		non_coding_transcript_exon	Exon 11 of 13
	FAH	ENST00000261755.9	TSL:5	c.1056C>T	p.Ser352Ser	synonymous	Exon 13 of 15	ENSP00000261755.5

Frequencies

GnomAD3 genomes AF: 0.0538 AC: 8179 AN: 152118 Hom.: 295 Cov.: 32

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

GnomAD2 exomes AF: 0.0573 AC: 13961 AN: 243748 AF XY: 0.0570

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 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.: 32 AF XY: 0.0504 AC XY: 36480 AN XY: 723236

African (AFR) AF: 0.0370 AC: 1237 AN: 33464

American (AMR) AF: 0.0711 AC: 3179 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0231 AC: 604 AN: 26128

East Asian (EAS) AF: 0.0791 AC: 3138 AN: 39692

South Asian (SAS) AF: 0.0537 AC: 4628 AN: 86234

European-Finnish (FIN) AF: 0.0968 AC: 4407 AN: 45512

Middle Eastern (MID) AF: 0.0758 AC: 436 AN: 5752

European-Non Finnish (NFE) AF: 0.0469 AC: 52176 AN: 1111318

Other (OTH) AF: 0.0506 AC: 3049 AN: 60286

GnomAD4 genome AF: 0.0537 AC: 8179 AN: 152236 Hom.: 296 Cov.: 32 AF XY: 0.0576 AC XY: 4284 AN XY: 74420

African (AFR) AF: 0.0360 AC: 1494 AN: 41544

American (AMR) AF: 0.0700 AC: 1072 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0230 AC: 80 AN: 3472

East Asian (EAS) AF: 0.0871 AC: 451 AN: 5176

South Asian (SAS) AF: 0.0595 AC: 287 AN: 4826

European-Finnish (FIN) AF: 0.114 AC: 1207 AN: 10600

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0500 AC: 3401 AN: 67996

Other (OTH) AF: 0.0701 AC: 148 AN: 2112

Alfa AF: 0.0439 Hom.: 144

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

Submissions by phenotype

not specified Benign:6

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.

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

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

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.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Tyrosinemia type I Benign:3

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.

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	3.9
DANN	Benign	0.59
PhyloP100		0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs1801374; hg19: chr15-80472561; COSMIC: COSV55721855;