NM_025074.7:c.11717T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_025074.7(FRAS1):c.11717T>C(p.Ile3906Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0178 in 1,613,872 control chromosomes in the GnomAD database, including 302 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. I3906I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.014 ( 18 hom., cov: 32)

Exomes 𝑓: 0.018 ( 284 hom. )

Consequence

FRAS1
NM_025074.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 6.12

Publications

6 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007147819).

BP6

Variant 4-78540802-T-C is Benign according to our data. Variant chr4-78540802-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 547870. Variant chr4-78540802-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 547870. Variant chr4-78540802-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 547870.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0138 (2100/152318) while in subpopulation NFE AF = 0.0213 (1447/68022). AF 95% confidence interval is 0.0204. There are 18 homozygotes in GnomAd4. There are 1007 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 18 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRAS1	NM_025074.7 link	c.11717T>C	p.Ile3906Thr	missense_variant	Exon 74 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.11717T>C	p.Ile3906Thr	missense_variant	Exon 74 of 74	5	NM_025074.7	ENSP00000422834.2		Q86XX4-2

Frequencies

GnomAD3 genomes

AF:

0.0138

AC:

2101

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00357

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.0153

Gnomad ASJ

AF:

0.0141

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00663

Gnomad FIN

AF:

0.0134

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0213

Gnomad OTH

AF:

0.0125

GnomAD2 exomes

AF:

0.0135

AC:

3366

AN:

249138

AF XY:

0.0140

show subpopulations

Gnomad AFR exome

AF:

0.00330

Gnomad AMR exome

AF:

0.00948

Gnomad ASJ exome

AF:

0.0124

Gnomad EAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.0117

Gnomad NFE exome

AF:

0.0201

Gnomad OTH exome

AF:

0.0205

GnomAD4 exome

AF:

0.0183

AC:

26707

AN:

1461554

Hom.:

284

Cov.:

AF XY:

0.0180

AC XY:

13097

AN XY:

727038

show subpopulations

African (AFR)

AF:

0.00311

AC:

104

AN:

33476

American (AMR)

AF:

0.0101

AC:

451

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0111

AC:

290

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.00820

AC:

707

AN:

86258

European-Finnish (FIN)

AF:

0.0120

AC:

642

AN:

53398

Middle Eastern (MID)

AF:

0.0219

AC:

126

AN:

5762

European-Non Finnish (NFE)

AF:

0.0209

AC:

23233

AN:

1111742

Other (OTH)

AF:

0.0191

AC:

1150

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

1547

3094

4641

6188

7735

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

852

1704

2556

3408

4260

<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:

0.0138

AC:

2100

AN:

152318

Hom.:

Cov.:

AF XY:

0.0135

AC XY:

1007

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00356

AC:

148

AN:

41570

American (AMR)

AF:

0.0153

AC:

234

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0141

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00664

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0134

AC:

142

AN:

10622

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0213

AC:

1447

AN:

68022

Other (OTH)

AF:

0.0123

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

109

218

327

436

545

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0181

Hom.:

Bravo

AF:

0.0145

TwinsUK

AF:

0.0175

AC:

ALSPAC

AF:

0.0213

AC:

ESP6500AA

AF:

0.00402

AC:

ESP6500EA

AF:

0.0185

AC:

155

ExAC

AF:

0.0132

AC:

1593

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.0228

EpiControl

AF:

0.0200

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Fraser syndrome 1

Uncertain:1Benign: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. -

Mar 15, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BA1, BS2, BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.96

Eigen

Benign

0.031

Eigen_PC

Benign

0.088

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.77

MetaRNN

Benign

0.0071

MetaSVM

Benign

-1.0

PhyloP100

6.1

PrimateAI

Benign

0.39

Sift4G

Uncertain

0.0070

Vest4

0.21

ClinPred

0.042

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.26

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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