rs758398734

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_031433.4(MFRP):c.1148C>T(p.Pro383Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000412 in 1,455,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P383R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

MFRP
NM_031433.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.66

Publications

0 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14074403).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MFRP	NM_031433.4 link	c.1148C>T	p.Pro383Leu	missense_variant	Exon 10 of 15	ENST00000619721.6	NP_113621.1	Q9BY79-1
C1QTNF5	NM_015645.5 link	c.-1489C>T		5_prime_UTR_variant	Exon 10 of 15		NP_056460.1	Q9BXJ0A0A024R3F8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MFRP	ENST00000619721.6 link	c.1148C>T	p.Pro383Leu	missense_variant	Exon 10 of 15	1	NM_031433.4	ENSP00000481824.1	Q9BY79-1
MFRP	ENST00000360167.4 link	c.922C>T	p.Pro308Ser	missense_variant	Exon 8 of 10	2		ENSP00000353291.4	Q9BY79-2
MFRP	ENST00000449574.7 link	c.-2C>T		5_prime_UTR_variant	Exon 1 of 4	5		ENSP00000391664.3	A0A0X1KG76

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000412

AC:

AN:

1455708

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723738

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33394

American (AMR)

AF:

0.00

AC:

AN:

43912

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26008

East Asian (EAS)

AF:

0.00

AC:

AN:

39498

South Asian (SAS)

AF:

0.00

AC:

AN:

85358

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51936

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5358

European-Non Finnish (NFE)

AF:

0.00000541

AC:

AN:

1110074

Other (OTH)

AF:

0.00

AC:

AN:

60170

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Isolated microphthalmia 5

Uncertain:1

Mar 10, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 935506). This variant has not been reported in the literature in individuals affected with MFRP-related conditions. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 383 of the MFRP protein (p.Pro383Leu). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.23

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.62

M_CAP

Benign

0.011

MetaRNN

Benign

0.14

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

PhyloP100

2.7

Sift4G

Benign

0.13

Polyphen

0.059

Vest4

0.27

MutPred

0.55

Loss of disorder (P = 0.0244);

MVP

0.39

ClinPred

0.39

GERP RS

0.56

PromoterAI

-0.030

Neutral

(source)

Varity_R

0.037

gMVP

0.44

Mutation Taster

=294/6

polymorphism

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over