rs12512164

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_025074.7(FRAS1):c.3406G>A(p.Glu1136Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.263 in 1,613,212 control chromosomes in the GnomAD database, including 57,385 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.24 ( 4821 hom., cov: 32)

Exomes 𝑓: 0.26 ( 52564 hom. )

Consequence

FRAS1
NM_025074.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 3.31

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005619079).

BP6

Variant 4-78379839-G-A is Benign according to our data. Variant chr4-78379839-G-A is described in ClinVar as [Benign]. Clinvar id is 196042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-78379839-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.298 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FRAS1	NM_025074.7 linkuse as main transcript	c.3406G>A	p.Glu1136Lys	missense_variant	27/74	ENST00000512123.4	NP_079350.5	Q86XX4-2
FRAS1	NM_001166133.2 linkuse as main transcript	c.3406G>A	p.Glu1136Lys	missense_variant	27/42		NP_001159605.1	Q86XX4-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
FRAS1	ENST00000512123.4 linkuse as main transcript	c.3406G>A	p.Glu1136Lys	missense_variant	27/74	5	NM_025074.7	ENSP00000422834.2	Q86XX4-2
FRAS1	ENST00000325942.11 linkuse as main transcript	c.3406G>A	p.Glu1136Lys	missense_variant	27/42	1		ENSP00000326330.6	Q86XX4-5
FRAS1	ENST00000682513.1 linkuse as main transcript	c.3406G>A	p.Glu1136Lys	missense_variant	27/64			ENSP00000508201.1	A0A804HL50
FRAS1	ENST00000684159.1 linkuse as main transcript	c.3406G>A	p.Glu1136Lys	missense_variant	27/45			ENSP00000506875.1	A0A804HI32

Frequencies

GnomAD3 genomes

AF:

0.242

AC:

36694

AN:

151878

Hom.:

4816

Cov.:

show subpopulations

Gnomad AFR

AF:

0.146

Gnomad AMI

AF:

0.295

Gnomad AMR

AF:

0.305

Gnomad ASJ

AF:

0.267

Gnomad EAS

AF:

0.207

Gnomad SAS

AF:

0.195

Gnomad FIN

AF:

0.314

Gnomad MID

AF:

0.237

Gnomad NFE

AF:

0.277

Gnomad OTH

AF:

0.264

GnomAD3 exomes

AF:

0.269

AC:

66797

AN:

248708

Hom.:

9596

AF XY:

0.263

AC XY:

35506

AN XY:

134920

show subpopulations

Gnomad AFR exome

AF:

0.141

Gnomad AMR exome

AF:

0.366

Gnomad ASJ exome

AF:

0.262

Gnomad EAS exome

AF:

0.216

Gnomad SAS exome

AF:

0.188

Gnomad FIN exome

AF:

0.311

Gnomad NFE exome

AF:

0.279

Gnomad OTH exome

AF:

0.269

GnomAD4 exome

AF:

0.265

AC:

386883

AN:

1461216

Hom.:

52564

Cov.:

AF XY:

0.263

AC XY:

191152

AN XY:

726904

show subpopulations

Gnomad4 AFR exome

AF:

0.143

Gnomad4 AMR exome

AF:

0.362

Gnomad4 ASJ exome

AF:

0.263

Gnomad4 EAS exome

AF:

0.216

Gnomad4 SAS exome

AF:

0.189

Gnomad4 FIN exome

AF:

0.315

Gnomad4 NFE exome

AF:

0.271

Gnomad4 OTH exome

AF:

0.250

GnomAD4 genome

AF:

0.242

AC:

36720

AN:

151996

Hom.:

4821

Cov.:

AF XY:

0.242

AC XY:

17995

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.146

Gnomad4 AMR

AF:

0.305

Gnomad4 ASJ

AF:

0.267

Gnomad4 EAS

AF:

0.207

Gnomad4 SAS

AF:

0.196

Gnomad4 FIN

AF:

0.314

Gnomad4 NFE

AF:

0.277

Gnomad4 OTH

AF:

0.266

Alfa

AF:

0.269

Hom.:

13825

Bravo

AF:

0.241

TwinsUK

AF:

0.267

AC:

990

ALSPAC

AF:

0.268

AC:

1034

ESP6500AA

AF:

0.148

AC:

560

ESP6500EA

AF:

0.275

AC:

2256

ExAC

AF:

0.264

AC:

31918

Asia WGS

AF:

0.202

AC:

708

AN:

3476

EpiCase

AF:

0.272

EpiControl

AF:

0.269

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 18, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Fraser syndrome 1

Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.90

Eigen

Benign

-0.049

Eigen_PC

Benign

-0.024

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.82

T;T

MetaRNN

Benign

0.0056

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

M;M

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.9

N;.

REVEL

Benign

0.27

Sift

Benign

0.29

T;.

Sift4G

Benign

0.75

T;T

Vest4

0.36

ClinPred

0.021

GERP RS

3.5

gMVP

0.47

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