4-78482528-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_025074.7(FRAS1):c.8745C>T(p.Phe2915Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 1,612,948 control chromosomes in the GnomAD database, including 37,424 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 4207 hom., cov: 33)

Exomes 𝑓: 0.20 ( 33217 hom. )

Consequence

FRAS1
NM_025074.7 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.18

Publications

10 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.138).

BP6

Variant 4-78482528-C-T is Benign according to our data. Variant chr4-78482528-C-T is described in ClinVar as Benign. ClinVar VariationId is 261816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.18 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.323 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRAS1	NM_025074.7 link	c.8745C>T	p.Phe2915Phe	synonymous_variant	Exon 58 of 74	ENST00000512123.4	NP_079350.5	Q86XX4-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRAS1	ENST00000512123.4 link	c.8745C>T	p.Phe2915Phe	synonymous_variant	Exon 58 of 74	5	NM_025074.7	ENSP00000422834.2		Q86XX4-2
FRAS1	ENST00000682513.1 link	c.8745C>T	p.Phe2915Phe	synonymous_variant	Exon 58 of 64			ENSP00000508201.1		A0A804HL50

Frequencies

GnomAD3 genomes

AF:

0.220

AC:

33423

AN:

152012

Hom.:

4204

Cov.:

show subpopulations

Gnomad AFR

AF:

0.327

Gnomad AMI

AF:

0.203

Gnomad AMR

AF:

0.153

Gnomad ASJ

AF:

0.122

Gnomad EAS

AF:

0.00366

Gnomad SAS

AF:

0.0569

Gnomad FIN

AF:

0.158

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.214

Gnomad OTH

AF:

0.198

GnomAD2 exomes

AF:

0.163

AC:

40480

AN:

248552

AF XY:

0.159

show subpopulations

Gnomad AFR exome

AF:

0.331

Gnomad AMR exome

AF:

0.0937

Gnomad ASJ exome

AF:

0.128

Gnomad EAS exome

AF:

0.00245

Gnomad FIN exome

AF:

0.162

Gnomad NFE exome

AF:

0.216

Gnomad OTH exome

AF:

0.169

GnomAD4 exome

AF:

0.203

AC:

296670

AN:

1460818

Hom.:

33217

Cov.:

AF XY:

0.198

AC XY:

143856

AN XY:

726656

show subpopulations

African (AFR)

AF:

0.326

AC:

10899

AN:

33460

American (AMR)

AF:

0.102

AC:

4533

AN:

44644

Ashkenazi Jewish (ASJ)

AF:

0.125

AC:

3273

AN:

26122

East Asian (EAS)

AF:

0.00239

AC:

AN:

39684

South Asian (SAS)

AF:

0.0643

AC:

5530

AN:

86000

European-Finnish (FIN)

AF:

0.165

AC:

8796

AN:

53394

Middle Eastern (MID)

AF:

0.113

AC:

652

AN:

5764

European-Non Finnish (NFE)

AF:

0.226

AC:

251662

AN:

1111396

Other (OTH)

AF:

0.186

AC:

11230

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

11676

23352

35029

46705

58381

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8562

17124

25686

34248

42810

<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:

0.220

AC:

33457

AN:

152130

Hom.:

4207

Cov.:

AF XY:

0.212

AC XY:

15761

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.327

AC:

13565

AN:

41466

American (AMR)

AF:

0.152

AC:

2330

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.122

AC:

425

AN:

3470

East Asian (EAS)

AF:

0.00367

AC:

AN:

5184

South Asian (SAS)

AF:

0.0568

AC:

274

AN:

4826

European-Finnish (FIN)

AF:

0.158

AC:

1676

AN:

10578

Middle Eastern (MID)

AF:

0.0884

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.214

AC:

14542

AN:

67994

Other (OTH)

AF:

0.196

AC:

415

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1303

2607

3910

5214

6517

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

324

648

972

1296

1620

<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:

0.217

Hom.:

2557

Bravo

AF:

0.223

Asia WGS

AF:

0.0560

AC:

197

AN:

3478

EpiCase

AF:

0.200

EpiControl

AF:

0.206

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Fraser syndrome 1

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.79

PhyloP100

1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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