rs745597204

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_025074.7(FRAS1):c.7551T>A(p.Tyr2517Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,613,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

FRAS1
NM_025074.7 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: -0.489

Variant links:

Genes affected

FRAS1 (HGNC:19185): (Fraser extracellular matrix complex subunit 1) This gene encodes an extracellular matrix protein that appears to function in the regulation of epidermal-basement membrane adhesion and organogenesis during development. Mutations in this gene cause Fraser syndrome, a multisystem malformation that can include craniofacial, urogenital and respiratory system abnormalities. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

FRAS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-78473466-T-A is Pathogenic according to our data. Variant chr4-78473466-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235484.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=4, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRAS1	NM_025074.7 linkuse as main transcript	c.7551T>A	p.Tyr2517Ter	stop_gained	53/74	ENST00000512123.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRAS1	ENST00000512123.4 linkuse as main transcript	c.7551T>A	p.Tyr2517Ter	stop_gained	53/74	5	NM_025074.7	P1	Q86XX4-2
FRAS1	ENST00000682513.1 linkuse as main transcript	c.7551T>A	p.Tyr2517Ter	stop_gained	53/64

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000202

AC:

AN:

247526

Hom.:

AF XY:

0.00000744

AC XY:

AN XY:

134444

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000359

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000349

AC:

AN:

1461236

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

726896

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000441

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 10, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 30, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 27, 2023	This sequence change creates a premature translational stop signal (p.Tyr2517*) in the FRAS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FRAS1 are known to be pathogenic (PMID: 12766769, 18671281). This variant is present in population databases (rs745597204, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with Fraser syndrome (PMID: 18671281). ClinVar contains an entry for this variant (Variation ID: 235484). For these reasons, this variant has been classified as Pathogenic. -

Fraser syndrome 1

Pathogenic:1Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Aug 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 18, 2018	The FRAS1 c.7551T>A (p.Tyr2517Ter) variant is a stop-gained variant that is expected to result in an absent or truncated protein. It has been reported in a heterozygous state in one individual with Fraser syndrome (van Haelst et al. 2008). Control data are unavailable for this variant, which is reported at a frequency of 0.000045 in the European (non-Finnish) population of the Exome Aggregation Consortium. The evidence for this variant is limited. Due to the potential impact of stop-gained variants and the supporting evidence, the p.Tyr2517Ter variant is classified as a variant of unknown significance but suspicious for pathogenicity for Fraser syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Congenital anomaly of kidney and urinary tract

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Sydney Genome Diagnostics, Children's Hospital Westmead

Nov 22, 2018

This individual is heterozygous for the c.7551T>A variant in the FRAS1 gene. This variant creates a premature stop codon p.(Tyr2517*) and may result in a null allele due to nonsense-mediated mRNA decay. This variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with a very low allele frequency of 0.002% (5 out of 244, 500 alleles). The variant has been previously reported in a patient with Fraser syndrome (Haelst et al Am J Med Genet A. 2008 Sep 1;146A(17):2252-2257) and has also been listed on ClinVar to be pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/235484/). This variant is considered to be a pathogenic according to the ACMG guidelines. (Evidence used: PVS1, PM2, PP5). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Uncertain

0.11

Cadd

Pathogenic

Dann

Benign

0.94

Eigen

Benign

-0.83

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.29

MutationTaster

Benign

1.0

Vest4

0.98

ClinPred

0.89

GERP RS

-6.5

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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