11-119339435-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001278431.2(C1QTNF5):c.628G>C(p.Gly210Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. G210D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: C1QTNF5 NM_001278431.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.18

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a domain C1q (size 139) in uniprot entity C1QT5_HUMAN there are 17 pathogenic changes around while only 4 benign (81%) in NM_001278431.2
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C1QTNF5	NM_001278431.2	c.628G>C	p.Gly210Arg	missense_variant	3/3	ENST00000528368.3
MFRP	NM_031433.4	c.*1524G>C		3_prime_UTR_variant	15/15	ENST00000619721.6
C1QTNF5	NM_015645.5	c.628G>C	p.Gly210Arg	missense_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C1QTNF5	ENST00000528368.3	c.628G>C	p.Gly210Arg	missense_variant	3/3	1	NM_001278431.2	P1
C1QTNF5	ENST00000530681.2	c.628G>C	p.Gly210Arg	missense_variant	2/2	1		P1
MFRP	ENST00000619721.6	c.*1524G>C		3_prime_UTR_variant	15/15	1	NM_031433.4	P1
C1QTNF5	ENST00000525657.2	n.518G>C		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinal dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jul 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;D
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Uncertain	-0.030	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	0.78	D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0040	D;T
Sift4G	Uncertain	0.018	D;D
Vest4		0.57
MutPred		0.50		Loss of catalytic residue at V211 (P = 0.0313);Loss of catalytic residue at V211 (P = 0.0313);
MVP		0.66
ClinPred		0.95	D
GERP RS		4.4
Varity_R		0.52
gMVP		0.61

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: rs1379281803; hg19: chr11-119210145;