rs7996253

chr13-38878856-C-T

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.8885C>T(p.Ala2962Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00344 in 1,614,096 control chromosomes in the GnomAD database, including 183 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A2962A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.019 (105 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (78 hom.)
• Consequence: FREM2 NM_207361.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.19

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=0.0034364462).
• BP6: Variant 13-38878856-C-T is Benign according to our data. Variant chr13-38878856-C-T is described in ClinVar as [Benign]. Clinvar id is 235742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-38878856-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.064 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FREM2	NM_207361.6	c.8885C>T	p.Ala2962Val	missense_variant	23/24	ENST00000280481.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FREM2	ENST00000280481.9	c.8885C>T	p.Ala2962Val	missense_variant	23/24	1	NM_207361.6	P1

Frequencies

GnomAD3 genomes AF: 0.0186 AC: 2834 AN: 152160 Hom.: 106 Cov.: 33

Gnomad AFR AF: 0.0660

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00908

GnomAD3 exomes AF: 0.00475 AC: 1194 AN: 251424 Hom.: 35 AF XY: 0.00332 AC XY: 451 AN XY: 135876

Gnomad AFR exome AF: 0.0658

Gnomad AMR exome AF: 0.00289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00185 AC: 2702 AN: 1461818 Hom.: 78 Cov.: 33 AF XY: 0.00157 AC XY: 1145 AN XY: 727218

Gnomad4 AFR exome AF: 0.0664

Gnomad4 AMR exome AF: 0.00277

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000710

Gnomad4 OTH exome AF: 0.00401

GnomAD4 genome AF: 0.0187 AC: 2844 AN: 152278 Hom.: 105 Cov.: 33 AF XY: 0.0184 AC XY: 1369 AN XY: 74448

Gnomad4 AFR AF: 0.0660

Gnomad4 AMR AF: 0.00471

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.00350 Hom.: 36

Bravo AF: 0.0208

ESP6500AA AF: 0.0660 AC: 291

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00597 AC: 725

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 19, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 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	0.13
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	20
Dann	Uncertain	0.99
Eigen	Benign	0.11
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.94	D
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.11
Sift	Benign	0.16	T
Sift4G	Benign	0.27	T
Vest4		0.24
MVP		0.64
MPC		0.12
ClinPred		0.021	T
GERP RS		2.8
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs7996253; hg19: chr13-39452993;