rs2496424

chr13-38690460-T-Achr13-38690460-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_207361.6(FREM2):c.3116T>A(p.Met1039Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00301 in 1,614,196 control chromosomes in the GnomAD database, including 139 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (71 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (68 hom.)
• Consequence: FREM2 NM_207361.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.47

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=0.0028074384).
• BP6: Variant 13-38690460-T-A is Benign according to our data. Variant chr13-38690460-T-A is described in ClinVar as [Benign]. Clinvar id is 235588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0563 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FREM2	NM_207361.6	c.3116T>A	p.Met1039Lys	missense_variant	1/24	ENST00000280481.9
FREM2	XM_017020554.2	c.3116T>A	p.Met1039Lys	missense_variant	1/3
FREM2	XR_941571.3	n.3384T>A		non_coding_transcript_exon_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FREM2	ENST00000280481.9	c.3116T>A	p.Met1039Lys	missense_variant	1/24	1	NM_207361.6	P1

Frequencies

GnomAD3 genomes AF: 0.0164 AC: 2489 AN: 152196 Hom.: 71 Cov.: 32

Gnomad AFR AF: 0.0582

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00418 AC: 1050 AN: 251480 Hom.: 25 AF XY: 0.00291 AC XY: 396 AN XY: 135916

Gnomad AFR exome AF: 0.0589

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000791

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00161 AC: 2358 AN: 1461882 Hom.: 68 Cov.: 36 AF XY: 0.00138 AC XY: 1003 AN XY: 727242

Gnomad4 AFR exome AF: 0.0598

Gnomad4 AMR exome AF: 0.00239

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.00331

GnomAD4 genome AF: 0.0164 AC: 2498 AN: 152314 Hom.: 71 Cov.: 32 AF XY: 0.0157 AC XY: 1170 AN XY: 74484

Gnomad4 AFR AF: 0.0582

Gnomad4 AMR AF: 0.00385

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.000744 Hom.: 3

Bravo AF: 0.0184

ESP6500AA AF: 0.0533 AC: 235

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00516 AC: 626

Asia WGS AF: 0.00289 AC: 11 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 04, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

Fraser syndrome 2 Benign:1

Benign, 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 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	0.070
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	5.2
Dann	Benign	0.54
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.59
FATHMM_MKL	Uncertain	0.90	D
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.092
Sift	Benign	0.90	T
Sift4G	Benign	0.86	T
Vest4		0.51
MVP		0.30
MPC		0.19
ClinPred		0.026	T
GERP RS		-2.7
gMVP		0.70

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: rs2496424; hg19: chr13-39264597; COSMIC: COSV99040174;