rs149376662

Positions:

chr11-119346126-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_031433.4(MFRP):c.191G>A(p.Arg64His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000978 in 1,603,600 control chromosomes in the GnomAD database, including 15 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R64R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0011 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00097 ( 13 hom. )

Consequence

MFRP
NM_031433.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: -1.47

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004893422).

BP6

Variant 11-119346126-C-T is Benign according to our data. Variant chr11-119346126-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 302978.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}. Variant chr11-119346126-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.00097 (1408/1451376) while in subpopulation EAS AF= 0.00535 (211/39406). AF 95% confidence interval is 0.00476. There are 13 homozygotes in gnomad4_exome. There are 709 alleles in male gnomad4_exome subpopulation. Median coverage is 36. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MFRP	NM_031433.4 link	c.191G>A	p.Arg64His	missense_variant	3/15	ENST00000619721.6	NP_113621.1	Q9BY79-1
C1QTNF5	NM_015645.5 link	c.-2446G>A		5_prime_UTR_variant	3/15		NP_056460.1	Q9BXJ0A0A024R3F8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MFRP	ENST00000619721.6 link	c.191G>A	p.Arg64His	missense_variant	3/15	1	NM_031433.4	ENSP00000481824.1		Q9BY79-1

Frequencies

GnomAD3 genomes

AF:

0.00105

AC:

160

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.0334

Gnomad EAS

AF:

0.00231

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.00240

GnomAD3 exomes

AF:

0.00151

AC:

341

AN:

225536

Hom.:

AF XY:

0.00147

AC XY:

180

AN XY:

122226

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000156

Gnomad ASJ exome

AF:

0.0288

Gnomad EAS exome

AF:

0.000408

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000413

Gnomad OTH exome

AF:

0.00194

GnomAD4 exome

AF:

0.000970

AC:

1408

AN:

1451376

Hom.:

Cov.:

AF XY:

0.000984

AC XY:

709

AN XY:

720874

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000117

Gnomad4 ASJ exome

AF:

0.0323

Gnomad4 EAS exome

AF:

0.00535

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000192

Gnomad4 NFE exome

AF:

0.000174

Gnomad4 OTH exome

AF:

0.00268

GnomAD4 genome

AF:

0.00105

AC:

160

AN:

152224

Hom.:

Cov.:

AF XY:

0.000967

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.0334

Gnomad4 EAS

AF:

0.00232

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00165

Hom.:

Bravo

AF:

0.000971

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00117

AC:

ExAC

AF:

0.00112

AC:

135

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Isolated microphthalmia 6

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Retinal degeneration

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

MFRP-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 18, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Isolated microphthalmia 5

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.60

CADD

Benign

5.8

DANN

Benign

0.94

DEOGEN2

Benign

0.019

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0046

LIST_S2

Benign

0.71

T;T

M_CAP

Benign

0.030

MetaRNN

Benign

0.0049

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.065

N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.46

.;N

REVEL

Benign

0.036

Sift

Benign

0.59

.;T

Sift4G

Benign

0.51

T;T

Polyphen

0.0010

B;.

Vest4

0.13

MVP

0.17

ClinPred

0.0080

GERP RS

-2.9

Varity_R

0.037

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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