rs111033578

chr11-119339574-G-Cchr11-119339574-G-T

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1_Very_Strong PM1 PP3_Moderate PP5_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 same amino acid change has been previously reported as Likely pathogenicin ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: C1QTNF5 NM_001278431.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 3.23

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]

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]

ACMG classification

Verdict is Pathogenic. Variant got 20 ACMG points.

• PS1: Transcript NM_001278431.2 (C1QTNF5) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 865771
• PM1: In a strand (size 21) in uniprot entity C1QT5_HUMAN there are 7 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/exons	MANE	UniProt
C1QTNF5	NM_001278431.2	c.489C>G	p.Ser163Arg	missense_variant	3/3	ENST00000528368.3
MFRP	NM_031433.4	c.*1385C>G		3_prime_UTR_variant	15/15	ENST00000619721.6
C1QTNF5	NM_015645.5	c.489C>G	p.Ser163Arg	missense_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C1QTNF5	ENST00000528368.3	c.489C>G	p.Ser163Arg	missense_variant	3/3	1	NM_001278431.2	P1
C1QTNF5	ENST00000530681.2	c.489C>G	p.Ser163Arg	missense_variant	2/2	1		P1
MFRP	ENST00000619721.6	c.*1385C>G		3_prime_UTR_variant	15/15	1	NM_031433.4	P1
C1QTNF5	ENST00000525657.2	n.379C>G		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461162 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 726898

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.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Late-onset retinal degeneration Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 15, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 17, 2023	Criteria applied: PS1,PS3,PS4_MOD,PM1_SUP,PM2_SUP,PP3 -
Pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	UCLA Clinical Genomics Center, UCLA	Jun 12, 2012	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 02, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 2020	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 17, 2021	- -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Mar 20, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T
Eigen	Benign	0.18
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	2.0	M;M
MutationTaster	Benign	0.94	A;A;A
PrimateAI	Pathogenic	0.81	D
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	D
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

Other links and lift over

dbSNP: rs111033578; hg19: chr11-119210284;