11-119345794-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_031433.4(MFRP):c.406G>A(p.Val136Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 1,613,314 control chromosomes in the GnomAD database, including 78,848 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.25 ( 5540 hom., cov: 32)

Exomes 𝑓: 0.31 ( 73308 hom. )

Consequence

MFRP
NM_031433.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.46

Publications

34 publications found

Variant links:

Genes affected

MFRP (HGNC:18121): (membrane frizzled-related protein) This gene encodes a member of the frizzled-related protein family. The encoded protein plays an important role in eye development and mutations in this gene have been associated with nanophthalmos, posterior microphthalmia, retinitis pigmentosa, foveoschisis, and optic disc drusen. The protein is encoded by a bicistronic transcript which also encodes C1q and tumor necrosis factor related protein 5 (C1QTNF5). [provided by RefSeq, Jun 2013]

MFRP links:

C1QTNF5 (HGNC:14344): (C1q and TNF related 5) This gene encodes a member of a family of proteins that function as components of basement membranes and may play a role in cell adhesion. Mutations in this gene have been associated with late-onset retinal degeneration. The protein may be encoded by either a bicistronic transcript including sequence from the upstream membrane frizzled-related protein gene (MFRP), or by a monocistronic transcript expressed from an internal promoter. [provided by RefSeq, Jun 2013]

C1QTNF5 Gene-Disease associations (from GenCC):

late-onset retinal degeneration
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P

C1QTNF5 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=0.004874885).

BP6

Variant 11-119345794-C-T is Benign according to our data. Variant chr11-119345794-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 167299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.329 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
MFRP	NM_031433.4 link	c.406G>A	p.Val136Met	missense_variant	Exon 4 of 15	ENST00000619721.6	NP_113621.1
C1QTNF5	NM_015645.5 link	c.-2231G>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 4 of 15		NP_056460.1
C1QTNF5	NM_015645.5 link	c.-2231G>A		5_prime_UTR_variant	Exon 4 of 15		NP_056460.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MFRP	ENST00000619721.6 link	c.406G>A	p.Val136Met	missense_variant	Exon 4 of 15	1	NM_031433.4	ENSP00000481824.1

Frequencies

GnomAD3 genomes

AF:

0.246

AC:

37345

AN:

151884

Hom.:

5541

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0890

Gnomad AMI

AF:

0.502

Gnomad AMR

AF:

0.221

Gnomad ASJ

AF:

0.310

Gnomad EAS

AF:

0.195

Gnomad SAS

AF:

0.214

Gnomad FIN

AF:

0.324

Gnomad MID

AF:

0.370

Gnomad NFE

AF:

0.332

Gnomad OTH

AF:

0.291

GnomAD2 exomes

AF:

0.265

AC:

65587

AN:

247454

AF XY:

0.273

show subpopulations

Gnomad AFR exome

AF:

0.0855

Gnomad AMR exome

AF:

0.164

Gnomad ASJ exome

AF:

0.303

Gnomad EAS exome

AF:

0.198

Gnomad FIN exome

AF:

0.311

Gnomad NFE exome

AF:

0.332

Gnomad OTH exome

AF:

0.288

GnomAD4 exome

AF:

0.311

AC:

454796

AN:

1461312

Hom.:

73308

Cov.:

AF XY:

0.311

AC XY:

225727

AN XY:

726938

show subpopulations

African (AFR)

AF:

0.0799

AC:

2675

AN:

33480

American (AMR)

AF:

0.174

AC:

7767

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.307

AC:

8016

AN:

26134

East Asian (EAS)

AF:

0.205

AC:

8152

AN:

39698

South Asian (SAS)

AF:

0.230

AC:

19837

AN:

86258

European-Finnish (FIN)

AF:

0.316

AC:

16742

AN:

52972

Middle Eastern (MID)

AF:

0.325

AC:

1875

AN:

5766

European-Non Finnish (NFE)

AF:

0.334

AC:

371465

AN:

1111894

Other (OTH)

AF:

0.303

AC:

18267

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

20032

40064

60095

80127

100159

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11734

23468

35202

46936

58670

<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:

0.246

AC:

37336

AN:

152002

Hom.:

5540

Cov.:

AF XY:

0.244

AC XY:

18112

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.0890

AC:

3691

AN:

41492

American (AMR)

AF:

0.220

AC:

3367

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.310

AC:

1073

AN:

3464

East Asian (EAS)

AF:

0.195

AC:

999

AN:

5134

South Asian (SAS)

AF:

0.215

AC:

1034

AN:

4812

European-Finnish (FIN)

AF:

0.324

AC:

3425

AN:

10562

Middle Eastern (MID)

AF:

0.364

AC:

107

AN:

294

European-Non Finnish (NFE)

AF:

0.332

AC:

22575

AN:

67948

Other (OTH)

AF:

0.289

AC:

610

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1362

2724

4087

5449

6811

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

398

796

1194

1592

1990

<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:

0.289

Hom.:

17206

Bravo

AF:

0.233

TwinsUK

AF:

0.345

AC:

1280

ALSPAC

AF:

0.331

AC:

1276

ESP6500AA

AF:

0.0975

AC:

429

ESP6500EA

AF:

0.323

AC:

2771

ExAC

AF:

0.265

AC:

32153

Asia WGS

AF:

0.189

AC:

657

AN:

3478

EpiCase

AF:

0.340

EpiControl

AF:

0.338

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Oct 15, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Isolated microphthalmia 5

Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Isolated microphthalmia 6

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal degeneration

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.011

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.025

T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0024

LIST_S2

Benign

0.57

T;T

MetaRNN

Benign

0.0049

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-1.1

N;N

PhyloP100

-2.5

PrimateAI

Benign

0.28

PROVEAN

Benign

0.0

.;N

REVEL

Benign

0.039

Sift

Benign

1.0

.;T

Sift4G

Benign

0.64

T;T

Polyphen

0.0080

B;.

Vest4

0.047

ClinPred

0.00030

GERP RS

-3.1

Varity_R

0.023

gMVP

0.26

Mutation Taster

=300/0

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