rs931606

Positions:

chr4-78522696-G-A

Variant summary

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

The NM_025074.7(FRAS1):c.10696G>A(p.Val3566Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.544 in 1,606,372 control chromosomes in the GnomAD database, including 239,713 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.52 ( 20748 hom., cov: 31)

Exomes 𝑓: 0.55 ( 218965 hom. )

Consequence

FRAS1
NM_025074.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.46

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=4.3782646E-5).

BP6

Variant 4-78522696-G-A is Benign according to our data. Variant chr4-78522696-G-A is described in ClinVar as [Benign]. Clinvar id is 261798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-78522696-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.575 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.10696G>A	p.Val3566Ile	missense_variant	69/74	ENST00000512123.4	NP_079350.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FRAS1	ENST00000512123.4 linkuse as main transcript	c.10696G>A	p.Val3566Ile	missense_variant	69/74	5	NM_025074.7	ENSP00000422834	P1	Q86XX4-2

Frequencies

GnomAD3 genomes

AF:

0.521

AC:

79152

AN:

151816

Hom.:

20740

Cov.:

show subpopulations

Gnomad AFR

AF:

0.510

Gnomad AMI

AF:

0.489

Gnomad AMR

AF:

0.472

Gnomad ASJ

AF:

0.562

Gnomad EAS

AF:

0.490

Gnomad SAS

AF:

0.593

Gnomad FIN

AF:

0.467

Gnomad MID

AF:

0.576

Gnomad NFE

AF:

0.542

Gnomad OTH

AF:

0.545

GnomAD3 exomes

AF:

0.521

AC:

125705

AN:

241368

Hom.:

33132

AF XY:

0.530

AC XY:

69318

AN XY:

130838

show subpopulations

Gnomad AFR exome

AF:

0.507

Gnomad AMR exome

AF:

0.427

Gnomad ASJ exome

AF:

0.570

Gnomad EAS exome

AF:

0.484

Gnomad SAS exome

AF:

0.598

Gnomad FIN exome

AF:

0.460

Gnomad NFE exome

AF:

0.541

Gnomad OTH exome

AF:

0.558

GnomAD4 exome

AF:

0.547

AC:

794994

AN:

1454438

Hom.:

218965

Cov.:

AF XY:

0.548

AC XY:

396481

AN XY:

723208

show subpopulations

Gnomad4 AFR exome

AF:

0.507

Gnomad4 AMR exome

AF:

0.435

Gnomad4 ASJ exome

AF:

0.574

Gnomad4 EAS exome

AF:

0.507

Gnomad4 SAS exome

AF:

0.596

Gnomad4 FIN exome

AF:

0.454

Gnomad4 NFE exome

AF:

0.553

Gnomad4 OTH exome

AF:

0.550

GnomAD4 genome

AF:

0.521

AC:

79204

AN:

151934

Hom.:

20748

Cov.:

AF XY:

0.517

AC XY:

38363

AN XY:

74262

show subpopulations

Gnomad4 AFR

AF:

0.510

Gnomad4 AMR

AF:

0.472

Gnomad4 ASJ

AF:

0.562

Gnomad4 EAS

AF:

0.491

Gnomad4 SAS

AF:

0.593

Gnomad4 FIN

AF:

0.467

Gnomad4 NFE

AF:

0.542

Gnomad4 OTH

AF:

0.545

Alfa

AF:

0.543

Hom.:

58940

Bravo

AF:

0.522

TwinsUK

AF:

0.559

AC:

2073

ALSPAC

AF:

0.558

AC:

2151

ESP6500AA

AF:

0.519

AC:

1938

ESP6500EA

AF:

0.545

AC:

4480

ExAC

AF:

0.519

AC:

62682

Asia WGS

AF:

0.502

AC:

1745

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	Genome-Nilou Lab	Aug 10, 2021	- -
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. -

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.18

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.11

MetaRNN

Benign

0.000044

MetaSVM

Benign

-0.93

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.69

Sift4G

Benign

1.0

Vest4

0.026

ClinPred

0.0091

GERP RS

4.9

gMVP

0.081

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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