rs9532292

chr13-38859469-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_207361.6(FREM2):c.7398A>G(p.Thr2466=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.342 in 1,613,642 control chromosomes in the GnomAD database, including 98,682 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12582 hom., cov: 31)
  • Exomes 𝑓: 0.34 (86100 hom.)
• Consequence: FREM2 NM_207361.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -6.37

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 13-38859469-A-G is Benign according to our data. Variant chr13-38859469-A-G is described in ClinVar as [Benign]. Clinvar id is 263301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-38859469-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-6.36 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.546 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FREM2	NM_207361.6	c.7398A>G	p.Thr2466=	synonymous_variant	14/24	ENST00000280481.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FREM2	ENST00000280481.9	c.7398A>G	p.Thr2466=	synonymous_variant	14/24	1	NM_207361.6	P1

Frequencies

GnomAD3 genomes AF: 0.391 AC: 59255 AN: 151738 Hom.: 12538 Cov.: 31

Gnomad AFR AF: 0.552

Gnomad AMI AF: 0.312

Gnomad AMR AF: 0.386

Gnomad ASJ AF: 0.409

Gnomad EAS AF: 0.384

Gnomad SAS AF: 0.447

Gnomad FIN AF: 0.248

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.313

Gnomad OTH AF: 0.364

GnomAD3 exomes AF: 0.373 AC: 93785 AN: 251218 Hom.: 18613 AF XY: 0.368 AC XY: 49986 AN XY: 135758

Gnomad AFR exome AF: 0.560

Gnomad AMR exome AF: 0.473

Gnomad ASJ exome AF: 0.410

Gnomad EAS exome AF: 0.383

Gnomad SAS exome AF: 0.453

Gnomad FIN exome AF: 0.258

Gnomad NFE exome AF: 0.313

Gnomad OTH exome AF: 0.348

GnomAD4 exome AF: 0.337 AC: 493132 AN: 1461786 Hom.: 86100 Cov.: 43 AF XY: 0.340 AC XY: 246915 AN XY: 727188

Gnomad4 AFR exome AF: 0.559

Gnomad4 AMR exome AF: 0.469

Gnomad4 ASJ exome AF: 0.403

Gnomad4 EAS exome AF: 0.386

Gnomad4 SAS exome AF: 0.447

Gnomad4 FIN exome AF: 0.259

Gnomad4 NFE exome AF: 0.316

Gnomad4 OTH exome AF: 0.351

GnomAD4 genome AF: 0.391 AC: 59353 AN: 151856 Hom.: 12582 Cov.: 31 AF XY: 0.389 AC XY: 28879 AN XY: 74228

Gnomad4 AFR AF: 0.552

Gnomad4 AMR AF: 0.387

Gnomad4 ASJ AF: 0.409

Gnomad4 EAS AF: 0.385

Gnomad4 SAS AF: 0.450

Gnomad4 FIN AF: 0.248

Gnomad4 NFE AF: 0.313

Gnomad4 OTH AF: 0.359

Alfa AF: 0.337 Hom.: 17936

Bravo AF: 0.412

Asia WGS AF: 0.412 AC: 1438 AN: 3478

EpiCase AF: 0.319

EpiControl AF: 0.317

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fraser syndrome 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Isolated cryptophthalmia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.090
Dann	Benign	0.47

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: rs9532292; hg19: chr13-39433606; COSMIC: COSV54828922;