chr4-78363540-C-T

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.2450C>T(p.Ala817Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.518 in 1,612,438 control chromosomes in the GnomAD database, including 225,496 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.43 ( 16251 hom., cov: 32)

Exomes 𝑓: 0.53 ( 209245 hom. )

Consequence

FRAS1
NM_025074.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.0720

Publications

39 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=1.239405E-5).

BP6

Variant 4-78363540-C-T is Benign according to our data. Variant chr4-78363540-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.552 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRAS1	NM_025074.7 link	c.2450C>T	p.Ala817Val	missense_variant	Exon 21 of 74	ENST00000512123.4	NP_079350.5	Q86XX4-2
FRAS1	NM_001166133.2 link	c.2450C>T	p.Ala817Val	missense_variant	Exon 21 of 42		NP_001159605.1	Q86XX4-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FRAS1	ENST00000512123.4 link	c.2450C>T	p.Ala817Val	missense_variant	Exon 21 of 74	5	NM_025074.7	ENSP00000422834.2	Q86XX4-2
FRAS1	ENST00000325942.11 link	c.2450C>T	p.Ala817Val	missense_variant	Exon 21 of 42	1		ENSP00000326330.6	Q86XX4-5
FRAS1	ENST00000682513.1 link	c.2450C>T	p.Ala817Val	missense_variant	Exon 21 of 64			ENSP00000508201.1	A0A804HL50
FRAS1	ENST00000684159.1 link	c.2450C>T	p.Ala817Val	missense_variant	Exon 21 of 45			ENSP00000506875.1	A0A804HI32

Frequencies

GnomAD3 genomes

AF:

0.433

AC:

65716

AN:

151902

Hom.:

16241

Cov.:

show subpopulations

Gnomad AFR

AF:

0.192

Gnomad AMI

AF:

0.538

Gnomad AMR

AF:

0.508

Gnomad ASJ

AF:

0.482

Gnomad EAS

AF:

0.202

Gnomad SAS

AF:

0.368

Gnomad FIN

AF:

0.586

Gnomad MID

AF:

0.373

Gnomad NFE

AF:

0.556

Gnomad OTH

AF:

0.452

GnomAD2 exomes

AF:

0.484

AC:

119468

AN:

246848

AF XY:

0.481

show subpopulations

Gnomad AFR exome

AF:

0.181

Gnomad AMR exome

AF:

0.551

Gnomad ASJ exome

AF:

0.485

Gnomad EAS exome

AF:

0.198

Gnomad FIN exome

AF:

0.589

Gnomad NFE exome

AF:

0.560

Gnomad OTH exome

AF:

0.506

GnomAD4 exome

AF:

0.527

AC:

769042

AN:

1460418

Hom.:

209245

Cov.:

AF XY:

0.522

AC XY:

379499

AN XY:

726422

show subpopulations

African (AFR)

AF:

0.177

AC:

5915

AN:

33462

American (AMR)

AF:

0.547

AC:

24402

AN:

44618

Ashkenazi Jewish (ASJ)

AF:

0.484

AC:

12617

AN:

26092

East Asian (EAS)

AF:

0.206

AC:

8167

AN:

39666

South Asian (SAS)

AF:

0.374

AC:

32200

AN:

86014

European-Finnish (FIN)

AF:

0.596

AC:

31734

AN:

53248

Middle Eastern (MID)

AF:

0.401

AC:

2311

AN:

5760

European-Non Finnish (NFE)

AF:

0.560

AC:

622605

AN:

1111222

Other (OTH)

AF:

0.482

AC:

29091

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

17563

35127

52690

70254

87817

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17112

34224

51336

68448

85560

<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:

0.433

AC:

65749

AN:

152020

Hom.:

16251

Cov.:

AF XY:

0.432

AC XY:

32119

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.191

AC:

7943

AN:

41490

American (AMR)

AF:

0.509

AC:

7782

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.482

AC:

1671

AN:

3468

East Asian (EAS)

AF:

0.203

AC:

1045

AN:

5160

South Asian (SAS)

AF:

0.368

AC:

1771

AN:

4808

European-Finnish (FIN)

AF:

0.586

AC:

6187

AN:

10550

Middle Eastern (MID)

AF:

0.367

AC:

108

AN:

294

European-Non Finnish (NFE)

AF:

0.556

AC:

37796

AN:

67932

Other (OTH)

AF:

0.451

AC:

955

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1733

3466

5200

6933

8666

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

594

1188

1782

2376

2970

<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:

0.512

Hom.:

92108

Bravo

AF:

0.419

TwinsUK

AF:

0.565

AC:

2094

ALSPAC

AF:

0.559

AC:

2155

ESP6500AA

AF:

0.188

AC:

800

ESP6500EA

AF:

0.548

AC:

4650

ExAC

AF:

0.477

AC:

57739

Asia WGS

AF:

0.281

AC:

983

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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

- -

Dec 03, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

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 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

- -

not provided

Benign:2

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:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.49

(source)

DANN

Benign

0.080

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.057

LIST_S2

Benign

0.72

T;T

MetaRNN

Benign

0.000012

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.65

N;N

PhyloP100

-0.072

PrimateAI

Benign

0.24

PROVEAN

Benign

0.55

N;.

REVEL

Benign

0.069

Sift

Benign

1.0

T;.

Sift4G

Benign

1.0

T;T

Vest4

0.034

ClinPred

0.0053

GERP RS

0.56

gMVP

0.50

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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