rs111033578

Variant names:

• chr11-119339574-G-C
• rs111033578
• NM_001278431.2:c.489C>G

Your query was ambiguous. Multiple possible variants found:

• chr11-119339574-G-C
• chr11-119339574-G-T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 21P and 1B. PS1_Very_Strong PM1 PP2 PP3_Moderate PP5_Very_Strong BS2_Supporting

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 Likely pathogenic in 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 O:1
• Conservation: PhyloP100: 3.23
• Publications: 65 publications found

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]

MFRP Gene-Disease associations (from GenCC):

• isolated microphthalmia 5

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, G2P, Orphanet
• nanophthalmos 2

  Inheritance: AR Classification: DEFINITIVE, MODERATE Submitted by: Ambry Genetics, G2P
• nanophthalmia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PS1: Transcript NM_001278431.2 (C1QTNF5) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a chain Complement C1q tumor necrosis factor-related protein 5 (size 227) in uniprot entity C1QT5_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_001278431.2
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 6 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Trascript score misZ: 0.7257 (below the threshold of 3.09). GenCC associations: The gene is linked to late-onset retinal degeneration.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 2126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 12 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278431.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1QTNF5	NM_001278431.2	MANE Select	c.489C>G	p.Ser163Arg	missense	Exon 3 of 3	NP_001265360.1
	MFRP	NM_031433.4	MANE Select	c.*1385C>G		3_prime_UTR	Exon 15 of 15	NP_113621.1
	C1QTNF5	NM_015645.5		c.489C>G	p.Ser163Arg	missense	Exon 15 of 15	NP_056460.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1QTNF5	ENST00000528368.3	TSL:1 MANE Select	c.489C>G	p.Ser163Arg	missense	Exon 3 of 3	ENSP00000431140.1
	C1QTNF5	ENST00000530681.2	TSL:1	c.489C>G	p.Ser163Arg	missense	Exon 2 of 2	ENSP00000456533.2
	MFRP	ENST00000619721.6	TSL:1 MANE Select	c.*1385C>G		3_prime_UTR	Exon 15 of 15	ENSP00000481824.1

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52706

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Late-onset retinal degeneration Pathogenic:4 Other:1

Jun 12, 2012

UCLA Clinical Genomics Center, UCLA

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant classified as Pathogenic and reported on 08-17-2022 by Blueprint Genetics. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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

Oct 15, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Pathogenic:3

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

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)

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 v4.9

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
Eigen	Benign	0.18
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	2.0	M
PhyloP100		3.2
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.6	N
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.011	D
Vest4		0.90
MutPred		0.81		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
Mutation Taster		=9/91	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs111033578; hg19: chr11-119210284;