13-38690553-T-C

Position:

chr13-38690553-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_207361.6(FREM2):c.3209T>C(p.Phe1070Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.303 in 1,613,692 control chromosomes in the GnomAD database, including 84,064 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.43 ( 17096 hom., cov: 33)

Exomes 𝑓: 0.29 ( 66968 hom. )

Consequence

FREM2
NM_207361.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.679

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.4487134E-6).

BP6

Variant 13-38690553-T-C is Benign according to our data. Variant chr13-38690553-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 193525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-38690553-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.745 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
FREM2	NM_207361.6 linkuse as main transcript	c.3209T>C	p.Phe1070Ser	missense_variant	1/24	ENST00000280481.9
FREM2	XM_017020554.2 linkuse as main transcript	c.3209T>C	p.Phe1070Ser	missense_variant	1/3
FREM2	XR_941571.3 linkuse as main transcript	n.3477T>C		non_coding_transcript_exon_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FREM2	ENST00000280481.9 linkuse as main transcript	c.3209T>C	p.Phe1070Ser	missense_variant	1/24	1	NM_207361.6	P1	Q5SZK8-1

Frequencies

GnomAD3 genomes

AF:

0.426

AC:

64680

AN:

152008

Hom.:

17039

Cov.:

show subpopulations

Gnomad AFR

AF:

0.752

Gnomad AMI

AF:

0.272

Gnomad AMR

AF:

0.419

Gnomad ASJ

AF:

0.307

Gnomad EAS

AF:

0.415

Gnomad SAS

AF:

0.299

Gnomad FIN

AF:

0.316

Gnomad MID

AF:

0.316

Gnomad NFE

AF:

0.265

Gnomad OTH

AF:

0.376

GnomAD3 exomes

AF:

0.342

AC:

85988

AN:

251426

Hom.:

16757

AF XY:

0.326

AC XY:

44307

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.763

Gnomad AMR exome

AF:

0.435

Gnomad ASJ exome

AF:

0.318

Gnomad EAS exome

AF:

0.399

Gnomad SAS exome

AF:

0.292

Gnomad FIN exome

AF:

0.314

Gnomad NFE exome

AF:

0.266

Gnomad OTH exome

AF:

0.322

GnomAD4 exome

AF:

0.291

AC:

424958

AN:

1461566

Hom.:

66968

Cov.:

AF XY:

0.288

AC XY:

209697

AN XY:

727080

show subpopulations

Gnomad4 AFR exome

AF:

0.764

Gnomad4 AMR exome

AF:

0.431

Gnomad4 ASJ exome

AF:

0.315

Gnomad4 EAS exome

AF:

0.384

Gnomad4 SAS exome

AF:

0.295

Gnomad4 FIN exome

AF:

0.316

Gnomad4 NFE exome

AF:

0.264

Gnomad4 OTH exome

AF:

0.318

GnomAD4 genome

AF:

0.426

AC:

64795

AN:

152126

Hom.:

17096

Cov.:

AF XY:

0.425

AC XY:

31634

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.752

Gnomad4 AMR

AF:

0.419

Gnomad4 ASJ

AF:

0.307

Gnomad4 EAS

AF:

0.415

Gnomad4 SAS

AF:

0.298

Gnomad4 FIN

AF:

0.316

Gnomad4 NFE

AF:

0.265

Gnomad4 OTH

AF:

0.375

Alfa

AF:

0.299

Hom.:

19413

Bravo

AF:

0.447

TwinsUK

AF:

0.265

AC:

984

ALSPAC

AF:

0.262

AC:

1011

ESP6500AA

AF:

0.752

AC:

3315

ESP6500EA

AF:

0.274

AC:

2360

ExAC

AF:

0.347

AC:

42146

Asia WGS

AF:

0.401

AC:

1396

AN:

3478

EpiCase

AF:

0.267

EpiControl

AF:

0.268

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 09, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -

Fraser syndrome 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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 provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	This variant is associated with the following publications: (PMID: 17000706) -

Isolated cryptophthalmia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

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

0.050

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.72

CADD

Benign

DANN

Benign

0.58

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.037

MetaRNN

Benign

0.0000014

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

PrimateAI

Benign

0.25

PROVEAN

Benign

0.60

REVEL

Benign

0.097

Sift

Benign

0.67

Sift4G

Benign

0.55

Vest4

0.014

MPC

0.21

ClinPred

0.0024

GERP RS

6.1

gMVP

0.33

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