rs111033578

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS1PM1PP3_ModeratePP5_Very_Strong

The NM_001278431.2(C1QTNF5):c.489C>G(p.Ser163Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

C1QTNF5
NM_001278431.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 3.23

Variant links:

Genes affected

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:

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PS1

Transcript NM_001278431.2 (C1QTNF5) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd

PM1

In a strand (size 21) in uniprot entity C1QT5_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001278431.2

PP3

MetaRNN computational evidence supports a deleterious effect, 0.913

PP5

Variant 11-119339574-G-C is Pathogenic according to our data. Variant chr11-119339574-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-119339574-G-C is described in Lovd as [Pathogenic]. Variant chr11-119339574-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C1QTNF5	NM_001278431.2 link	c.489C>G	p.Ser163Arg	missense_variant	Exon 3 of 3	ENST00000528368.3	NP_001265360.1	Q9BXJ0A0A024R3F8
MFRP	NM_031433.4 link	c.*1385C>G		3_prime_UTR_variant	Exon 15 of 15	ENST00000619721.6	NP_113621.1	Q9BY79-1
C1QTNF5	NM_015645.5 link	c.489C>G	p.Ser163Arg	missense_variant	Exon 15 of 15		NP_056460.1	Q9BXJ0A0A024R3F8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C1QTNF5	ENST00000528368.3 link	c.489C>G	p.Ser163Arg	missense_variant	Exon 3 of 3	1	NM_001278431.2	ENSP00000431140.1		Q9BXJ0
MFRP	ENST00000619721 link	c.*1385C>G		3_prime_UTR_variant	Exon 15 of 15	1	NM_031433.4	ENSP00000481824.1		Q9BY79-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461162

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

726898

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Late-onset retinal degeneration

Pathogenic:4

Jun 12, 2012

UCLA Clinical Genomics Center, UCLA

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 15, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Genomics England Pilot Project, Genomics England

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 17, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS1,PS3,PS4_MOD,PM1_SUP,PM2_SUP,PP3 -

not provided

Pathogenic:3

Jul 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 163 of the C1QTNF5 protein (p.Ser163Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with late-onset retinal degeneration (PMID: 12944416, 23289492, 29847639). It has also been observed to segregate with disease in related individuals. This variant is also known as c.686C>G. ClinVar contains an entry for this variant (Variation ID: 2126). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects C1QTNF5 function (PMID: 24531000). For these reasons, this variant has been classified as Pathogenic. -

Jan 29, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Most common pathogenic variant associated with late-onset retinal degeneration (Hayward et al., 2003; Stanton et al., 2017); Published functional studies demonstrate a damaging effect with aggregate formation in vitro and pathological effects in mice that were similar to patients with late-onset retinal degeneration (Hayward et al., 2003; Dinculescu et al., 2015); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29721928, 31385385, 29555955, 12944416, 26513502, 26197217, 22110650, 24531000, 22892318, 21349921, 23289492) -

Jun 17, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal dystrophy

Pathogenic:1

Mar 20, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

T;T

Eigen

Benign

0.18

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

.;D

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Uncertain

0.16

MutationAssessor

Benign

2.0

M;M

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-1.6

N;.

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0050

D;.

Sift4G

Uncertain

0.011

D;D

Vest4

0.90

MutPred

0.81

Gain of solvent accessibility (P = 0.1185);Gain of solvent accessibility (P = 0.1185);

MVP

0.84

ClinPred

0.97

GERP RS

2.2

Varity_R

0.84

gMVP

0.85

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

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