chr4-78466310-A-G

Variant names:

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.7132A>G(p.Lys2378Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.994 in 1,613,966 control chromosomes in the GnomAD database, including 797,199 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.97 ( 72262 hom., cov: 31)

Exomes 𝑓: 1.0 ( 724937 hom. )

Consequence

FRAS1
NM_025074.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 7.76

Publications

26 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=1.345344E-6).

BP6

Variant 4-78466310-A-G is Benign according to our data. Variant chr4-78466310-A-G is described in ClinVar as Benign. ClinVar VariationId is 261813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.992 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025074.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRAS1	NM_025074.7	MANE Select	c.7132A>G	p.Lys2378Glu	missense	Exon 50 of 74	NP_079350.5

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRAS1	ENST00000512123.4	TSL:5 MANE Select	c.7132A>G	p.Lys2378Glu	missense	Exon 50 of 74	ENSP00000422834.2
	FRAS1	ENST00000682513.1		c.7132A>G	p.Lys2378Glu	missense	Exon 50 of 64	ENSP00000508201.1

Frequencies

GnomAD3 genomes

AF:

0.974

AC:

148148

AN:

152168

Hom.:

72207

Cov.:

show subpopulations

Gnomad AFR

AF:

0.913

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.985

Gnomad ASJ

AF:

0.991

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

1.00

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.972

Gnomad NFE

AF:

0.998

Gnomad OTH

AF:

0.982

GnomAD2 exomes

AF:

0.991

AC:

247031

AN:

249202

AF XY:

0.993

show subpopulations

Gnomad AFR exome

AF:

0.904

Gnomad AMR exome

AF:

0.990

Gnomad ASJ exome

AF:

0.989

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

0.998

Gnomad OTH exome

AF:

0.994

GnomAD4 exome

AF:

0.996

AC:

1455619

AN:

1461680

Hom.:

724937

Cov.:

AF XY:

0.996

AC XY:

724433

AN XY:

727120

show subpopulations

African (AFR)

AF:

0.908

AC:

30383

AN:

33476

American (AMR)

AF:

0.989

AC:

44235

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.989

AC:

25844

AN:

26136

East Asian (EAS)

AF:

1.00

AC:

39696

AN:

39696

South Asian (SAS)

AF:

1.00

AC:

86243

AN:

86254

European-Finnish (FIN)

AF:

1.00

AC:

53401

AN:

53402

Middle Eastern (MID)

AF:

0.988

AC:

5695

AN:

5766

European-Non Finnish (NFE)

AF:

0.999

AC:

1110319

AN:

1111854

Other (OTH)

AF:

0.991

AC:

59803

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

309

618

927

1236

1545

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21670

43340

65010

86680

108350

<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:

0.974

AC:

148262

AN:

152286

Hom.:

72262

Cov.:

AF XY:

0.974

AC XY:

72537

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.913

AC:

37949

AN:

41546

American (AMR)

AF:

0.985

AC:

15071

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.991

AC:

3438

AN:

3468

East Asian (EAS)

AF:

1.00

AC:

5180

AN:

5180

South Asian (SAS)

AF:

1.00

AC:

4815

AN:

4816

European-Finnish (FIN)

AF:

1.00

AC:

10614

AN:

10616

Middle Eastern (MID)

AF:

0.969

AC:

285

AN:

294

European-Non Finnish (NFE)

AF:

0.998

AC:

67922

AN:

68042

Other (OTH)

AF:

0.982

AC:

2078

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

190

380

571

761

951

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

914

1828

2742

3656

4570

<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:

0.991

Hom.:

215845

Bravo

AF:

0.969

TwinsUK

AF:

0.998

AC:

3702

ALSPAC

AF:

0.998

AC:

3847

ESP6500AA

AF:

0.915

AC:

3940

ESP6500EA

AF:

0.997

AC:

8493

ExAC

AF:

0.990

AC:

119892

Asia WGS

AF:

0.993

AC:

3453

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Nov 09, 2016

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

not provided

Benign:3

Mar 03, 2015

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

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.

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.046

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.072

MetaRNN

Benign

0.0000013

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-1.2

PhyloP100

7.8

PrimateAI

Benign

0.47

Sift4G

Benign

0.74

Vest4

0.034

ClinPred

0.026

GERP RS

5.5

gMVP

0.19

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over