rs12504081

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.1396T>A(p.Leu466Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.355 in 1,609,308 control chromosomes in the GnomAD database, including 103,537 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 (★★).

Frequency

Genomes: 𝑓 0.32 ( 8159 hom., cov: 30)

Exomes 𝑓: 0.36 ( 95378 hom. )

Consequence

FRAS1
NM_025074.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.71

Publications

32 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=0.00140059).

BP6

Variant 4-78284545-T-A is Benign according to our data. Variant chr4-78284545-T-A is described in ClinVar as Benign. ClinVar VariationId is 261803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.369 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRAS1	NM_025074.7 link	c.1396T>A	p.Leu466Ile	missense_variant	Exon 13 of 74	ENST00000512123.4	NP_079350.5	Q86XX4-2
FRAS1	NM_001166133.2 link	c.1396T>A	p.Leu466Ile	missense_variant	Exon 13 of 42		NP_001159605.1	Q86XX4-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRAS1	ENST00000512123.4 link	c.1396T>A	p.Leu466Ile	missense_variant	Exon 13 of 74	5	NM_025074.7	ENSP00000422834.2		Q86XX4-2

Frequencies

GnomAD3 genomes

AF:

0.318

AC:

48337

AN:

151774

Hom.:

8153

Cov.:

show subpopulations

Gnomad AFR

AF:

0.196

Gnomad AMI

AF:

0.337

Gnomad AMR

AF:

0.377

Gnomad ASJ

AF:

0.373

Gnomad EAS

AF:

0.378

Gnomad SAS

AF:

0.333

Gnomad FIN

AF:

0.401

Gnomad MID

AF:

0.291

Gnomad NFE

AF:

0.358

Gnomad OTH

AF:

0.321

GnomAD2 exomes

AF:

0.360

AC:

88348

AN:

245648

AF XY:

0.358

show subpopulations

Gnomad AFR exome

AF:

0.188

Gnomad AMR exome

AF:

0.421

Gnomad ASJ exome

AF:

0.366

Gnomad EAS exome

AF:

0.382

Gnomad FIN exome

AF:

0.406

Gnomad NFE exome

AF:

0.361

Gnomad OTH exome

AF:

0.357

GnomAD4 exome

AF:

0.359

AC:

523535

AN:

1457416

Hom.:

95378

Cov.:

AF XY:

0.358

AC XY:

259651

AN XY:

724822

show subpopulations

African (AFR)

AF:

0.191

AC:

6345

AN:

33260

American (AMR)

AF:

0.416

AC:

18428

AN:

44292

Ashkenazi Jewish (ASJ)

AF:

0.375

AC:

9771

AN:

26052

East Asian (EAS)

AF:

0.385

AC:

15193

AN:

39476

South Asian (SAS)

AF:

0.325

AC:

27691

AN:

85300

European-Finnish (FIN)

AF:

0.403

AC:

21503

AN:

53374

Middle Eastern (MID)

AF:

0.326

AC:

1877

AN:

5756

European-Non Finnish (NFE)

AF:

0.362

AC:

402141

AN:

1109692

Other (OTH)

AF:

0.342

AC:

20586

AN:

60214

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

16368

32737

49105

65474

81842

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12792

25584

38376

51168

63960

<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:

0.318

AC:

48367

AN:

151892

Hom.:

8159

Cov.:

AF XY:

0.322

AC XY:

23879

AN XY:

74216

show subpopulations

African (AFR)

AF:

0.196

AC:

8132

AN:

41430

American (AMR)

AF:

0.377

AC:

5760

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.373

AC:

1293

AN:

3468

East Asian (EAS)

AF:

0.379

AC:

1951

AN:

5152

South Asian (SAS)

AF:

0.330

AC:

1585

AN:

4796

European-Finnish (FIN)

AF:

0.401

AC:

4225

AN:

10528

Middle Eastern (MID)

AF:

0.282

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.359

AC:

24353

AN:

67924

Other (OTH)

AF:

0.322

AC:

680

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1589

3178

4766

6355

7944

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

492

984

1476

1968

2460

<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:

0.312

Hom.:

2462

Bravo

AF:

0.314

TwinsUK

AF:

0.369

AC:

1368

ALSPAC

AF:

0.368

AC:

1417

ESP6500AA

AF:

0.186

AC:

762

ESP6500EA

AF:

0.348

AC:

2921

ExAC

AF:

0.349

AC:

42268

Asia WGS

AF:

0.340

AC:

1179

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 23, 2020

GeneDx

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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

- -

Aug 10, 2021

Genome-Nilou Lab

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 specified

Benign:2

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.0051

Eigen_PC

Benign

-0.023

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.73

T;T

MetaRNN

Benign

0.0014

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.5

L;L

PhyloP100

1.7

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.3

N;.

REVEL

Benign

0.11

Sift

Benign

0.15

T;.

Sift4G

Uncertain

0.021

D;T

Vest4

0.27

ClinPred

0.015

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.45

Mutation Taster

=90/10

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