NM_031433.4:c.770G>A

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.770G>A(p.Arg257His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00559 in 1,613,140 control chromosomes in the GnomAD database, including 383 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R257C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.028 ( 201 hom., cov: 33)

Exomes 𝑓: 0.0032 ( 182 hom. )

Consequence

MFRP
NM_031433.4 missense, splice_region

Scores

Splicing: ADA: 0.00003878

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.03

Publications

7 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=0.0015755296).

BP6

Variant 11-119344876-C-T is Benign according to our data. Variant chr11-119344876-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 198271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0948 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MFRP	NM_031433.4 link	c.770G>A	p.Arg257His	missense_variant, splice_region_variant	Exon 6 of 15	ENST00000619721.6	NP_113621.1	Q9BY79-1
C1QTNF5	NM_015645.5 link	c.-1867G>A		splice_region_variant	Exon 6 of 15		NP_056460.1	Q9BXJ0A0A024R3F8
C1QTNF5	NM_015645.5 link	c.-1867G>A		5_prime_UTR_variant	Exon 6 of 15		NP_056460.1	Q9BXJ0A0A024R3F8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MFRP	ENST00000619721.6 link	c.770G>A	p.Arg257His	missense_variant, splice_region_variant	Exon 6 of 15	1	NM_031433.4	ENSP00000481824.1	Q9BY79-1
MFRP	ENST00000360167.4 link	c.770G>A	p.Arg257His	missense_variant, splice_region_variant	Exon 6 of 10	2		ENSP00000353291.4	Q9BY79-2
MFRP	ENST00000529147.2 link	n.733G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 6	5
MFRP	ENST00000634542.1 link	n.*361G>A		downstream_gene_variant		3		ENSP00000488979.1	A0A0U1RQG2

Frequencies

GnomAD3 genomes

AF:

0.0280

AC:

4261

AN:

152122

Hom.:

196

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0968

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00870

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00674

Gnomad SAS

AF:

0.00476

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.0215

GnomAD2 exomes

AF:

0.00843

AC:

2061

AN:

244618

AF XY:

0.00660

show subpopulations

Gnomad AFR exome

AF:

0.0984

Gnomad AMR exome

AF:

0.00494

Gnomad ASJ exome

AF:

0.000202

Gnomad EAS exome

AF:

0.00752

Gnomad FIN exome

AF:

0.0000467

Gnomad NFE exome

AF:

0.000268

Gnomad OTH exome

AF:

0.00399

GnomAD4 exome

AF:

0.00323

AC:

4715

AN:

1460900

Hom.:

182

Cov.:

AF XY:

0.00290

AC XY:

2107

AN XY:

726714

show subpopulations

African (AFR)

AF:

0.0970

AC:

3248

AN:

33480

American (AMR)

AF:

0.00539

AC:

241

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.000191

AC:

AN:

26128

East Asian (EAS)

AF:

0.00776

AC:

308

AN:

39694

South Asian (SAS)

AF:

0.00407

AC:

351

AN:

86222

European-Finnish (FIN)

AF:

0.0000190

AC:

AN:

52624

Middle Eastern (MID)

AF:

0.00607

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000998

AC:

111

AN:

1111934

Other (OTH)

AF:

0.00687

AC:

415

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

290

580

871

1161

1451

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

220

330

440

550

<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:

0.0282

AC:

4295

AN:

152240

Hom.:

201

Cov.:

AF XY:

0.0269

AC XY:

2006

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0973

AC:

4039

AN:

41494

American (AMR)

AF:

0.00869

AC:

133

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00675

AC:

AN:

5184

South Asian (SAS)

AF:

0.00477

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

68024

Other (OTH)

AF:

0.0213

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

200

399

599

798

998

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.0125

Hom.:

195

Bravo

AF:

0.0309

ESP6500AA

AF:

0.0958

AC:

421

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0102

AC:

1238

Asia WGS

AF:

0.0170

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27884173, 18648522, 20981092) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Feb 23, 2015

Eurofins Ntd Llc (ga)

Significance: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

- -

Isolated microphthalmia 5

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Late-onset retinal degeneration

Benign:1

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.022

T;.

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.15

T;T

MetaRNN

Benign

0.0016

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-2.2

N;N

PhyloP100

3.0

PrimateAI

Benign

0.33

PROVEAN

Benign

0.61

.;N

REVEL

Benign

0.10

Sift

Benign

0.73

.;T

Sift4G

Benign

0.99

T;T

Polyphen

0.0

B;.

Vest4

0.14

ClinPred

0.012

GERP RS

4.9

Varity_R

0.035

gMVP

0.21

Mutation Taster

=292/8

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000039

dbscSNV1_RF

Benign

0.0020

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