rs116099212

chr13-38878873-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 14/18 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.13

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]

ACMG classification

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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FREM2	NM_207361.6	c.8902G>A	p.Val2968Ile	missense_variant	23/24	ENST00000280481.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FREM2	ENST00000280481.9	c.8902G>A	p.Val2968Ile	missense_variant	23/24	1	NM_207361.6	P1

Frequencies

GnomAD3 genomes AF: 0.00375 AC: 570 AN: 152184 Hom.: 2 Cov.: 33

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.: 5 AF XY: 0.00433 AC XY: 588 AN XY: 135884

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.: 49 Cov.: 33 AF XY: 0.00605 AC XY: 4397 AN XY: 727226

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.: 2 Cov.: 33 AF XY: 0.00380 AC XY: 283 AN XY: 74464

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.: 11

Bravo AF: 0.00375

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00640 AC: 55

ExAC AF: 0.00400 AC: 486

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00622

EpiControl AF: 0.00658

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 29, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 09, 2019	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) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	FREM2: BP4, BS2 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 03, 2022	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 01, 2014	- -

FREM2-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 06, 2019

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). -

Isolated cryptophthalmia;C4540036:Fraser syndrome 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 08, 2022

- -

Fraser syndrome 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

Fraser syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	13
Dann	Benign	0.93
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.53
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.0065	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.99	D
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.056
Sift	Benign	0.080	T
Sift4G	Benign	0.21	T
Vest4		0.65
MVP		0.43
MPC		0.095
ClinPred		0.0029	T
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

Other links and lift over

dbSNP: rs116099212; hg19: chr13-39453010;