rs1868463

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_207361.6(FREM2):c.5003G>A(p.Arg1668His) variant causes a missense change. The variant allele was found at a frequency of 0.0623 in 1,603,678 control chromosomes in the GnomAD database, including 5,201 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.060 ( 434 hom., cov: 32)

Exomes 𝑓: 0.063 ( 4767 hom. )

Consequence

FREM2
NM_207361.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 4.93

Publications

20 publications found

Variant links:

Genes affected

FREM2 (HGNC:25396): (FRAS1 related extracellular matrix 2) This gene encodes an integral membrane protein containing numerous CSPG (chondroitin sulfate proteoglycan element) repeats and Calx-beta domains. The encoded protein localizes to the basement membrane, forming a ternary complex that plays a role in epidermal-dermal interactions. This protein is important for the integrity of skin and renal epithelia. Mutations in this gene are associated with Fraser syndrome. [provided by RefSeq, Apr 2014]

FREM2 Gene-Disease associations (from GenCC):

Fraser syndrome 2
Inheritance: AR Classification: DEFINITIVE, MODERATE Submitted by: G2P, Ambry Genetics
Fraser syndrome 1
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
renal agenesis, unilateral
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Fraser syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

FREM2 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=0.001679182).

BP6

Variant 13-38692347-G-A is Benign according to our data. Variant chr13-38692347-G-A is described in ClinVar as [Benign]. Clinvar id is 193534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FREM2	NM_207361.6 link	c.5003G>A	p.Arg1668His	missense_variant	Exon 1 of 24	ENST00000280481.9	NP_997244.4	Q5SZK8-1
FREM2	XM_017020554.2 link	c.5003G>A	p.Arg1668His	missense_variant	Exon 1 of 3		XP_016876043.1
FREM2	XR_941571.3 link	n.5271G>A		non_coding_transcript_exon_variant	Exon 1 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FREM2	ENST00000280481.9 link	c.5003G>A	p.Arg1668His	missense_variant	Exon 1 of 24	1	NM_207361.6	ENSP00000280481.7		Q5SZK8-1

Frequencies

GnomAD3 genomes

AF:

0.0600

AC:

9115

AN:

152028

Hom.:

433

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0437

Gnomad AMI

AF:

0.0833

Gnomad AMR

AF:

0.0589

Gnomad ASJ

AF:

0.142

Gnomad EAS

AF:

0.239

Gnomad SAS

AF:

0.185

Gnomad FIN

AF:

0.0221

Gnomad MID

AF:

0.161

Gnomad NFE

AF:

0.0479

Gnomad OTH

AF:

0.0809

GnomAD2 exomes

AF:

0.0786

AC:

19187

AN:

244034

AF XY:

0.0844

show subpopulations

Gnomad AFR exome

AF:

0.0434

Gnomad AMR exome

AF:

0.0366

Gnomad ASJ exome

AF:

0.146

Gnomad EAS exome

AF:

0.235

Gnomad FIN exome

AF:

0.0185

Gnomad NFE exome

AF:

0.0505

Gnomad OTH exome

AF:

0.0756

GnomAD4 exome

AF:

0.0625

AC:

90777

AN:

1451532

Hom.:

4767

Cov.:

AF XY:

0.0666

AC XY:

48029

AN XY:

720976

show subpopulations

African (AFR)

AF:

0.0486

AC:

1605

AN:

33052

American (AMR)

AF:

0.0391

AC:

1710

AN:

43768

Ashkenazi Jewish (ASJ)

AF:

0.142

AC:

3603

AN:

25360

East Asian (EAS)

AF:

0.262

AC:

10388

AN:

39580

South Asian (SAS)

AF:

0.175

AC:

14863

AN:

84852

European-Finnish (FIN)

AF:

0.0193

AC:

1026

AN:

53066

Middle Eastern (MID)

AF:

0.167

AC:

951

AN:

5694

European-Non Finnish (NFE)

AF:

0.0469

AC:

51943

AN:

1106350

Other (OTH)

AF:

0.0784

AC:

4688

AN:

59810

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

4356

8713

13069

17426

21782

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0599

AC:

9118

AN:

152146

Hom.:

434

Cov.:

AF XY:

0.0621

AC XY:

4621

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.0436

AC:

1808

AN:

41510

American (AMR)

AF:

0.0589

AC:

900

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.142

AC:

494

AN:

3472

East Asian (EAS)

AF:

0.239

AC:

1228

AN:

5148

South Asian (SAS)

AF:

0.185

AC:

892

AN:

4810

European-Finnish (FIN)

AF:

0.0221

AC:

234

AN:

10592

Middle Eastern (MID)

AF:

0.160

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0479

AC:

3259

AN:

68006

Other (OTH)

AF:

0.0852

AC:

180

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

427

853

1280

1706

2133

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0594

Hom.:

1429

Bravo

AF:

0.0615

TwinsUK

AF:

0.0453

AC:

168

ALSPAC

AF:

0.0493

AC:

190

ESP6500AA

AF:

0.0431

AC:

190

ESP6500EA

AF:

0.0509

AC:

438

ExAC

AF:

0.0809

AC:

9816

Asia WGS

AF:

0.199

AC:

691

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

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

- -

Nov 11, 2018

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

- -

not specified

Benign:2

Nov 15, 2014

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

- -

Fraser syndrome 2

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

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.42

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.95

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.1

PhyloP100

4.9

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.21

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.010

Vest4

0.24

MPC

0.53

ClinPred

0.022

GERP RS

4.5

gMVP

0.59

Mutation Taster

=91/9

polymorphism (auto)

(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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rs1868463

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