rs145881139

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_031433.4(MFRP):c.1374G>T(p.Leu458Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00817 in 1,613,338 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0089 ( 13 hom., cov: 33)

Exomes 𝑓: 0.0081 ( 74 hom. )

Consequence

MFRP
NM_031433.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.0310

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:):

C1QTNF5 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=0.005207181).

BP6

Variant 11-119342609-C-A is Benign according to our data. Variant chr11-119342609-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 261961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-119342609-C-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00891 (1356/152216) while in subpopulation AMR AF= 0.0117 (179/15302). AF 95% confidence interval is 0.0103. There are 13 homozygotes in gnomad4. There are 617 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MFRP	NM_031433.4 linkuse as main transcript	c.1374G>T	p.Leu458Phe	missense_variant	11/15	ENST00000619721.6	NP_113621.1
C1QTNF5	NM_015645.5 linkuse as main transcript	c.-1263G>T		5_prime_UTR_variant	11/15		NP_056460.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MFRP	ENST00000619721.6 linkuse as main transcript	c.1374G>T	p.Leu458Phe	missense_variant	11/15	1	NM_031433.4	ENSP00000481824	P1	Q9BY79-1
MFRP	ENST00000360167.4 linkuse as main transcript	c.1148G>T	p.Cys383Phe	missense_variant	9/10	2		ENSP00000353291		Q9BY79-2
MFRP	ENST00000449574.7 linkuse as main transcript	c.246G>T	p.Leu82Phe	missense_variant	2/4	5		ENSP00000391664

Frequencies

GnomAD3 genomes

AF:

0.00892

AC:

1357

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00645

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0118

Gnomad ASJ

AF:

0.0309

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00704

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.0102

Gnomad OTH

AF:

0.0182

GnomAD3 exomes

AF:

0.00818

AC:

2008

AN:

245552

Hom.:

AF XY:

0.00839

AC XY:

1122

AN XY:

133652

show subpopulations

Gnomad AFR exome

AF:

0.00567

Gnomad AMR exome

AF:

0.00703

Gnomad ASJ exome

AF:

0.0293

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00845

Gnomad FIN exome

AF:

0.00214

Gnomad NFE exome

AF:

0.00929

Gnomad OTH exome

AF:

0.0113

GnomAD4 exome

AF:

0.00809

AC:

11817

AN:

1461122

Hom.:

Cov.:

AF XY:

0.00829

AC XY:

6024

AN XY:

726840

show subpopulations

Gnomad4 AFR exome

AF:

0.00642

Gnomad4 AMR exome

AF:

0.00810

Gnomad4 ASJ exome

AF:

0.0276

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00772

Gnomad4 FIN exome

AF:

0.00216

Gnomad4 NFE exome

AF:

0.00800

Gnomad4 OTH exome

AF:

0.0109

GnomAD4 genome

AF:

0.00891

AC:

1356

AN:

152216

Hom.:

Cov.:

AF XY:

0.00829

AC XY:

617

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.00645

Gnomad4 AMR

AF:

0.0117

Gnomad4 ASJ

AF:

0.0309

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00704

Gnomad4 FIN

AF:

0.00151

Gnomad4 NFE

AF:

0.0102

Gnomad4 OTH

AF:

0.0180

Alfa

AF:

0.0108

Hom.:

Bravo

AF:

0.00956

TwinsUK

AF:

0.0102

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.00659

AC:

ESP6500EA

AF:

0.0106

AC:

ExAC

AF:

0.00822

AC:

997

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0121

EpiControl

AF:

0.0114

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	C1QTNF5: BS1, BS2; MFRP: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Retinal degeneration

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Isolated microphthalmia 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.35

MetaRNN

Benign

0.0052

MetaSVM

Benign

-0.86

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.16

REVEL

Benign

0.11

Sift

Benign

0.039

Sift4G

Uncertain

0.043

Vest4

0.37

MVP

0.35

ClinPred

0.029

GERP RS

2.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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