chr13-38690553-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 14/19 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:9

Conservation

PhyloP100: 0.679

Publications

37 publications found

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 Gene-Disease associations (from GenCC):

Fraser syndrome 2
Inheritance: AR Classification: DEFINITIVE, MODERATE Submitted by: G2P, Ambry Genetics
Fraser syndrome 1
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
renal agenesis, unilateral
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Fraser syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

FREM2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 193525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FREM2	NM_207361.6 link	c.3209T>C	p.Phe1070Ser	missense_variant	Exon 1 of 24	ENST00000280481.9	NP_997244.4	Q5SZK8-1
FREM2	XM_017020554.2 link	c.3209T>C	p.Phe1070Ser	missense_variant	Exon 1 of 3		XP_016876043.1
FREM2	XR_941571.3 link	n.3477T>C		non_coding_transcript_exon_variant	Exon 1 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FREM2	ENST00000280481.9 link	c.3209T>C	p.Phe1070Ser	missense_variant	Exon 1 of 24	1	NM_207361.6	ENSP00000280481.7		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

GnomAD2 exomes

AF:

0.342

AC:

85988

AN:

251426

AF XY:

0.326

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 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

African (AFR)

AF:

0.764

AC:

25564

AN:

33476

American (AMR)

AF:

0.431

AC:

19278

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.315

AC:

8238

AN:

26134

East Asian (EAS)

AF:

0.384

AC:

15257

AN:

39700

South Asian (SAS)

AF:

0.295

AC:

25405

AN:

86248

European-Finnish (FIN)

AF:

0.316

AC:

16863

AN:

53372

Middle Eastern (MID)

AF:

0.273

AC:

1572

AN:

5768

European-Non Finnish (NFE)

AF:

0.264

AC:

293584

AN:

1111766

Other (OTH)

AF:

0.318

AC:

19197

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

19332

38663

57995

77326

96658

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10274

20548

30822

41096

51370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.426

AC:

64795

AN:

152126

Hom.:

17096

Cov.:

AF XY:

0.425

AC XY:

31634

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.752

AC:

31212

AN:

41490

American (AMR)

AF:

0.419

AC:

6409

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.307

AC:

1063

AN:

3466

East Asian (EAS)

AF:

0.415

AC:

2144

AN:

5166

South Asian (SAS)

AF:

0.298

AC:

1440

AN:

4832

European-Finnish (FIN)

AF:

0.316

AC:

3346

AN:

10578

Middle Eastern (MID)

AF:

0.333

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.265

AC:

18044

AN:

67988

Other (OTH)

AF:

0.375

AC:

793

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1622

3243

4865

6486

8108

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

540

1080

1620

2160

2700

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.322

Hom.:

32244

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:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 11, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 17000706) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Dec 03, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 09, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Fraser syndrome 2

Benign:2

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Isolated cryptophthalmia

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Fraser syndrome 1

Benign:1

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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

PhyloP100

0.68

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

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over