rs116099212

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_207361.6(FREM2):c.8902G>A(p.Val2968Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00584 in 1,614,122 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0037 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0061 ( 49 hom. )

Consequence

FREM2
NM_207361.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 2.13

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0065407753).

BP6

Variant 13-38878873-G-A is Benign according to our data. Variant chr13-38878873-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 195789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-38878873-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00375 (571/152302) while in subpopulation NFE AF= 0.00669 (455/68028). AF 95% confidence interval is 0.00618. There are 2 homozygotes in gnomad4. There are 283 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FREM2	NM_207361.6 link	c.8902G>A	p.Val2968Ile	missense_variant	Exon 23 of 24	ENST00000280481.9	NP_997244.4	Q5SZK8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FREM2	ENST00000280481.9 link	c.8902G>A	p.Val2968Ile	missense_variant	Exon 23 of 24	1	NM_207361.6	ENSP00000280481.7		Q5SZK8-1

Frequencies

GnomAD3 genomes

AF:

0.00375

AC:

570

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00106

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.00160

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00667

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00406

AC:

1021

AN:

251420

Hom.:

AF XY:

0.00433

AC XY:

588

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.00171

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00503

Gnomad FIN exome

AF:

0.00259

Gnomad NFE exome

AF:

0.00630

Gnomad OTH exome

AF:

0.00358

GnomAD4 exome

AF:

0.00606

AC:

8854

AN:

1461820

Hom.:

Cov.:

AF XY:

0.00605

AC XY:

4397

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.000687

Gnomad4 AMR exome

AF:

0.00148

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00514

Gnomad4 FIN exome

AF:

0.00331

Gnomad4 NFE exome

AF:

0.00704

Gnomad4 OTH exome

AF:

0.00485

GnomAD4 genome

AF:

0.00375

AC:

571

AN:

152302

Hom.:

Cov.:

AF XY:

0.00380

AC XY:

283

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00106

Gnomad4 AMR

AF:

0.00203

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00310

Gnomad4 FIN

AF:

0.00160

Gnomad4 NFE

AF:

0.00669

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00616

Hom.:

Bravo

AF:

0.00375

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00640

AC:

ExAC

AF:

0.00400

AC:

486

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.00622

EpiControl

AF:

0.00658

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Sep 29, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely 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

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FREM2 p.Val2968Ile variant was not identified in Cosmic but was identified in dbSNP (ID: rs116099212), ClinVar (classified as benign by EGL Genetic Diagnostics and likely benign by Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics) and LOVD 3.0 (classified as likely benign). The variant was identified in control databases in 1149 of 282828 chromosomes (6 homozygous) at a frequency of 0.004063 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 811 of 129136 chromosomes (freq: 0.00628), South Asian in 154 of 30616 chromosomes (freq: 0.00503), Other in 28 of 7226 chromosomes (freq: 0.003875), European (Finnish) in 67 of 25122 chromosomes (freq: 0.002667), Latino in 61 of 35438 chromosomes (freq: 0.001721), African in 24 of 24974 chromosomes (freq: 0.000961), Ashkenazi Jewish in 3 of 10364 chromosomes (freq: 0.00029), and East Asian in 1 of 19952 chromosomes (freq: 0.00005). This variant was identified in the heterozygous state in one case with a prenatal diagnosis of laryngeal atresia/stenosis although the clinical significance of this variant is not known (Drury_2015_PMID:26275891). The p.Val2968 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Sep 09, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26275891) -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FREM2: BP4, BS2 -

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

Dec 01, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 03, 2022

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FREM2 c.8902G>A (p.Val2968Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0041 in 282828 control chromosomes in the gnomAD database, with 6 homozygotes. The variant occurs predominantly at a frequency of 0.0063 within the Non-Finnish European subpopulation in the gnomAD database, with 3 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in FREM2 causing Cryptophthalmos Syndrome phenotype (0.0013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Five ClinVar submitters have assessed the variant since 2014: three classified the variant as likely benign and two as benign. Based on the evidence outlined above, the variant was classified as benign. -

Isolated cryptophthalmia;C4540036:Fraser syndrome 2

Benign:1

Apr 08, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fraser syndrome 2

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

FREM2-related disorder

Benign:1

May 06, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Fraser syndrome 1

Benign:1

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.93

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.53

FATHMM_MKL

Uncertain

0.89

M_CAP

Benign

0.010

MetaRNN

Benign

0.0065

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.41

REVEL

Benign

0.056

Sift

Benign

0.080

Sift4G

Benign

0.21

Vest4

0.65

MVP

0.43

MPC

0.095

ClinPred

0.0029

GERP RS

1.2

gMVP

0.14

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over