rs12504081

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.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. 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 0.32 ( 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:7

Conservation

PhyloP100: 1.71

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=0.00140059).

BP6

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

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/exons	MANE	UniProt
FRAS1	NM_025074.7 linkuse as main transcript	c.1396T>A	p.Leu466Ile	missense_variant	13/74	ENST00000512123.4
FRAS1	NM_001166133.2 linkuse as main transcript	c.1396T>A	p.Leu466Ile	missense_variant	13/42

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRAS1	ENST00000512123.4 linkuse as main transcript	c.1396T>A	p.Leu466Ile	missense_variant	13/74	5	NM_025074.7	P1	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

GnomAD3 exomes

AF:

0.360

AC:

88348

AN:

245648

Hom.:

16189

AF XY:

0.358

AC XY:

47675

AN XY:

133298

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 SAS exome

AF:

0.326

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

Gnomad4 AFR exome

AF:

0.191

Gnomad4 AMR exome

AF:

0.416

Gnomad4 ASJ exome

AF:

0.375

Gnomad4 EAS exome

AF:

0.385

Gnomad4 SAS exome

AF:

0.325

Gnomad4 FIN exome

AF:

0.403

Gnomad4 NFE exome

AF:

0.362

Gnomad4 OTH exome

AF:

0.342

GnomAD4 genome

AF:

0.318

AC:

48367

AN:

151892

Hom.:

8159

Cov.:

AF XY:

0.322

AC XY:

23879

AN XY:

74216

show subpopulations

Gnomad4 AFR

AF:

0.196

Gnomad4 AMR

AF:

0.377

Gnomad4 ASJ

AF:

0.373

Gnomad4 EAS

AF:

0.379

Gnomad4 SAS

AF:

0.330

Gnomad4 FIN

AF:

0.401

Gnomad4 NFE

AF:

0.359

Gnomad4 OTH

AF:

0.322

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:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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 13, 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 specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.47

CADD

Benign

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

MutationTaster

Benign

0.72

P;P;P

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

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