rs145881139

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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. 14/18 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

Publications

9 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=0.005207181).

BP6

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

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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MFRP	NM_031433.4 link	c.1374G>T	p.Leu458Phe	missense_variant	Exon 11 of 15	ENST00000619721.6	NP_113621.1
C1QTNF5	NM_015645.5 link	c.-1263G>T		5_prime_UTR_variant	Exon 11 of 15		NP_056460.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MFRP	ENST00000619721.6 link	c.1374G>T	p.Leu458Phe	missense_variant	Exon 11 of 15	1	NM_031433.4	ENSP00000481824.1
MFRP	ENST00000360167.4 link	c.1148G>T	p.Cys383Phe	missense_variant	Exon 9 of 10	2		ENSP00000353291.4
MFRP	ENST00000449574.7 link	c.243G>T	p.Leu81Phe	missense_variant	Exon 2 of 4	5		ENSP00000391664.3

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

GnomAD2 exomes

AF:

0.00818

AC:

2008

AN:

245552

AF XY:

0.00839

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 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

African (AFR)

AF:

0.00642

AC:

215

AN:

33480

American (AMR)

AF:

0.00810

AC:

362

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.0276

AC:

721

AN:

26124

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.00772

AC:

666

AN:

86240

European-Finnish (FIN)

AF:

0.00216

AC:

114

AN:

52886

Middle Eastern (MID)

AF:

0.0314

AC:

181

AN:

5766

European-Non Finnish (NFE)

AF:

0.00800

AC:

8900

AN:

1111894

Other (OTH)

AF:

0.0109

AC:

657

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

704

1407

2111

2814

3518

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

306

612

918

1224

1530

<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:

0.00891

AC:

1356

AN:

152216

Hom.:

Cov.:

AF XY:

0.00829

AC XY:

617

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.00645

AC:

268

AN:

41540

American (AMR)

AF:

0.0117

AC:

179

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0309

AC:

107

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00704

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00151

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0102

AC:

693

AN:

67970

Other (OTH)

AF:

0.0180

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

135

202

270

337

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0101

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

C1QTNF5: BS1, BS2; MFRP: BP4, BS1, BS2 -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

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

- -

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

- -

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

(source)

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

PhyloP100

-0.031

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

PromoterAI

-0.013

Neutral

(source)

Varity_R

0.19

Mutation Taster

=99/1

polymorphism

(source)

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

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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