4-78534560-C-G

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.11037C>G(p.Pro3679Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.455 in 1,608,114 control chromosomes in the GnomAD database, including 173,625 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P3679P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.43 ( 15028 hom., cov: 33)

Exomes 𝑓: 0.46 ( 158597 hom. )

Consequence

FRAS1
NM_025074.7 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.527

Publications

24 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=0.023).

BP6

Variant 4-78534560-C-G is Benign according to our data. Variant chr4-78534560-C-G is described in ClinVar as Benign. ClinVar VariationId is 261801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.527 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.774 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRAS1	NM_025074.7 link	c.11037C>G	p.Pro3679Pro	synonymous_variant	Exon 71 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.11037C>G	p.Pro3679Pro	synonymous_variant	Exon 71 of 74	5	NM_025074.7	ENSP00000422834.2		Q86XX4-2

Frequencies

GnomAD3 genomes

AF:

0.434

AC:

65985

AN:

151966

Hom.:

15032

Cov.:

show subpopulations

Gnomad AFR

AF:

0.345

Gnomad AMI

AF:

0.348

Gnomad AMR

AF:

0.466

Gnomad ASJ

AF:

0.573

Gnomad EAS

AF:

0.794

Gnomad SAS

AF:

0.650

Gnomad FIN

AF:

0.443

Gnomad MID

AF:

0.570

Gnomad NFE

AF:

0.430

Gnomad OTH

AF:

0.466

GnomAD2 exomes

AF:

0.491

AC:

121945

AN:

248578

AF XY:

0.500

show subpopulations

Gnomad AFR exome

AF:

0.338

Gnomad AMR exome

AF:

0.469

Gnomad ASJ exome

AF:

0.579

Gnomad EAS exome

AF:

0.791

Gnomad FIN exome

AF:

0.437

Gnomad NFE exome

AF:

0.430

Gnomad OTH exome

AF:

0.493

GnomAD4 exome

AF:

0.458

AC:

666415

AN:

1456030

Hom.:

158597

Cov.:

AF XY:

0.464

AC XY:

336141

AN XY:

724566

show subpopulations

African (AFR)

AF:

0.348

AC:

11588

AN:

33328

American (AMR)

AF:

0.470

AC:

20953

AN:

44624

Ashkenazi Jewish (ASJ)

AF:

0.582

AC:

15182

AN:

26066

East Asian (EAS)

AF:

0.782

AC:

31021

AN:

39652

South Asian (SAS)

AF:

0.645

AC:

55545

AN:

86058

European-Finnish (FIN)

AF:

0.435

AC:

23190

AN:

53368

Middle Eastern (MID)

AF:

0.571

AC:

3287

AN:

5760

European-Non Finnish (NFE)

AF:

0.430

AC:

476322

AN:

1107006

Other (OTH)

AF:

0.487

AC:

29327

AN:

60168

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.420

Heterozygous variant carriers

17346

34692

52039

69385

86731

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14754

29508

44262

59016

73770

<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:

0.434

AC:

66005

AN:

152084

Hom.:

15028

Cov.:

AF XY:

0.441

AC XY:

32757

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.345

AC:

14304

AN:

41480

American (AMR)

AF:

0.466

AC:

7117

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.573

AC:

1990

AN:

3472

East Asian (EAS)

AF:

0.794

AC:

4108

AN:

5172

South Asian (SAS)

AF:

0.650

AC:

3131

AN:

4820

European-Finnish (FIN)

AF:

0.443

AC:

4674

AN:

10552

Middle Eastern (MID)

AF:

0.571

AC:

168

AN:

294

European-Non Finnish (NFE)

AF:

0.430

AC:

29212

AN:

67992

Other (OTH)

AF:

0.466

AC:

984

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1906

3812

5719

7625

9531

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

628

1256

1884

2512

3140

<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:

0.404

Hom.:

3842

Bravo

AF:

0.431

Asia WGS

AF:

0.675

AC:

2345

AN:

3478

EpiCase

AF:

0.452

EpiControl

AF:

0.454

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 06, 2020

GeneDx

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

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 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. -

not specified

Benign:2

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

9.3

(source)

DANN

Benign

0.67

PhyloP100

0.53

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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