rs61978626

Positions:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_207361.6(FREM2):c.7535G>A(p.Arg2512His) variant causes a missense change. The variant allele was found at a frequency of 0.00103 in 1,551,594 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00057 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 2 hom. )

Consequence

FREM2
NM_207361.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:5

Conservation

PhyloP100: 4.92

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 Likely_benign. Variant got -5 ACMG points.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000573 (86/150130) while in subpopulation NFE AF= 0.000991 (67/67626). AF 95% confidence interval is 0.0008. There are 1 homozygotes in gnomad4. There are 31 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FREM2	NM_207361.6 linkuse as main transcript	c.7535G>A	p.Arg2512His	missense_variant	15/24	ENST00000280481.9	NP_997244.4	Q5SZK8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FREM2	ENST00000280481.9 linkuse as main transcript	c.7535G>A	p.Arg2512His	missense_variant	15/24	1	NM_207361.6	ENSP00000280481.7		Q5SZK8-1

Frequencies

GnomAD3 genomes

AF:

0.000573

AC:

AN:

150026

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000270

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000335

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000215

Gnomad FIN

AF:

0.0000986

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000991

Gnomad OTH

AF:

0.000482

GnomAD3 exomes

AF:

0.000477

AC:

120

AN:

251370

Hom.:

AF XY:

0.000493

AC XY:

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000425

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000853

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00107

AC:

1505

AN:

1401464

Hom.:

Cov.:

AF XY:

0.00107

AC XY:

744

AN XY:

698296

show subpopulations

Gnomad4 AFR exome

AF:

0.000211

Gnomad4 AMR exome

AF:

0.0000473

Gnomad4 ASJ exome

AF:

0.0000787

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000235

Gnomad4 FIN exome

AF:

0.0000779

Gnomad4 NFE exome

AF:

0.00134

Gnomad4 OTH exome

AF:

0.000833

GnomAD4 genome

AF:

0.000573

AC:

AN:

150130

Hom.:

Cov.:

AF XY:

0.000423

AC XY:

AN XY:

73274

show subpopulations

Gnomad4 AFR

AF:

0.000269

Gnomad4 AMR

AF:

0.000334

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000215

Gnomad4 FIN

AF:

0.0000986

Gnomad4 NFE

AF:

0.000991

Gnomad4 OTH

AF:

0.000477

Alfa

AF:

0.000745

Hom.:

Bravo

AF:

0.000521

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000404

AC:

EpiCase

AF:

0.00109

EpiControl

AF:

0.000889

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 09, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 03, 2022	Variant summary: FREM2 c.7535G>A (p.Arg2512His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00048 in 251370 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in FREM2 causing Cryptophthalmos Syndrome (0.00048 vs 0.0013), allowing no conclusion about variant significance. c.7535G>A has been reported in the literature as a compound heterozygous genotype among mild recessive mutations identified in at-least one individual affected with isolated Congenital anomalies of the kidney and urinary tract (CAKUT (example, Kohl_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Cryptophthalmos Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Congenital anomaly of kidney and urinary tract

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Aug 24, 2018

- -

Isolated cryptophthalmia;C4540036:Fraser syndrome 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 26, 2024

- -

Fraser syndrome 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 18, 2022

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2512 of the FREM2 protein (p.Arg2512His). This variant is present in population databases (rs61978626, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of FREM2-related conditions (PMID: 24700879). ClinVar contains an entry for this variant (Variation ID: 435265). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.97

M_CAP

Benign

0.0082

MetaRNN

Uncertain

0.51

MetaSVM

Benign

-0.77

PrimateAI

Uncertain

0.48

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.29

Sift

Benign

0.12

Sift4G

Uncertain

0.012

Vest4

0.72

MVP

0.65

MPC

0.63

ClinPred

0.13

GERP RS

4.8

gMVP

0.65

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