rs12512164

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

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

Publications

34 publications found

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 Gene-Disease associations (from GenCC):

Fraser syndrome
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Fraser syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
renal agenesis, unilateral
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

FRAS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 196042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
FRAS1	NM_025074.7 link	c.3406G>A	p.Glu1136Lys	missense_variant	Exon 27 of 74	ENST00000512123.4	NP_079350.5
FRAS1	NM_001166133.2 link	c.3406G>A	p.Glu1136Lys	missense_variant	Exon 27 of 42		NP_001159605.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
FRAS1	ENST00000512123.4 link	c.3406G>A	p.Glu1136Lys	missense_variant	Exon 27 of 74	5	NM_025074.7	ENSP00000422834.2
FRAS1	ENST00000325942.11 link	c.3406G>A	p.Glu1136Lys	missense_variant	Exon 27 of 42	1		ENSP00000326330.6
FRAS1	ENST00000682513.1 link	c.3406G>A	p.Glu1136Lys	missense_variant	Exon 27 of 64			ENSP00000508201.1
FRAS1	ENST00000684159.1 link	c.3406G>A	p.Glu1136Lys	missense_variant	Exon 27 of 45			ENSP00000506875.1

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

GnomAD2 exomes

AF:

0.269

AC:

66797

AN:

248708

AF XY:

0.263

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 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

African (AFR)

AF:

0.143

AC:

4793

AN:

33472

American (AMR)

AF:

0.362

AC:

16171

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.263

AC:

6874

AN:

26128

East Asian (EAS)

AF:

0.216

AC:

8584

AN:

39694

South Asian (SAS)

AF:

0.189

AC:

16286

AN:

86240

European-Finnish (FIN)

AF:

0.315

AC:

16800

AN:

53386

Middle Eastern (MID)

AF:

0.233

AC:

1342

AN:

5760

European-Non Finnish (NFE)

AF:

0.271

AC:

300920

AN:

1111486

Other (OTH)

AF:

0.250

AC:

15113

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

15158

30316

45474

60632

75790

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9906

19812

29718

39624

49530

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.242

AC:

36720

AN:

151996

Hom.:

4821

Cov.:

AF XY:

0.242

AC XY:

17995

AN XY:

74284

show subpopulations

African (AFR)

AF:

0.146

AC:

6059

AN:

41466

American (AMR)

AF:

0.305

AC:

4658

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.267

AC:

927

AN:

3466

East Asian (EAS)

AF:

0.207

AC:

1065

AN:

5148

South Asian (SAS)

AF:

0.196

AC:

942

AN:

4810

European-Finnish (FIN)

AF:

0.314

AC:

3316

AN:

10554

Middle Eastern (MID)

AF:

0.224

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.277

AC:

18858

AN:

67958

Other (OTH)

AF:

0.266

AC:

561

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1367

2735

4102

5470

6837

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

388

776

1164

1552

1940

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.264

Hom.:

18888

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

Nov 18, 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

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Fraser syndrome 1

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 12, 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. -

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

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

PhyloP100

3.3

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

Mutation Taster

=87/13

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over