11-119339360-C-G

Variant names:

• chr11-119339360-C-G
• rs1298660906
• NM_001278431.2:c.703G>C

Variant summary

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

The NM_001278431.2(C1QTNF5):​c.703G>C​(p.Asp235His) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,700 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: C1QTNF5 NM_001278431.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.14

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 10 pathogenic changes around while only 2 benign (83%) in NM_001278431.2
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C1QTNF5	NM_001278431.2	c.703G>C	p.Asp235His	missense_variant	Exon 3 of 3	ENST00000528368.3	NP_001265360.1
MFRP	NM_031433.4	c.*1599G>C		3_prime_UTR_variant	Exon 15 of 15	ENST00000619721.6	NP_113621.1
C1QTNF5	NM_015645.5	c.703G>C	p.Asp235His	missense_variant	Exon 15 of 15		NP_056460.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C1QTNF5	ENST00000528368.3	c.703G>C	p.Asp235His	missense_variant	Exon 3 of 3	1	NM_001278431.2	ENSP00000431140.1
C1QTNF5	ENST00000530681.2	c.703G>C	p.Asp235His	missense_variant	Exon 2 of 2	1		ENSP00000456533.2
MFRP	ENST00000619721	c.*1599G>C		3_prime_UTR_variant	Exon 15 of 15	1	NM_031433.4	ENSP00000481824.1
C1QTNF5	ENST00000525657.2	n.*10G>C		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460700 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726534

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	.;D
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-4.0	D;.
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0040	D;.
Sift4G	Uncertain	0.0080	D;D
Vest4		0.44
MutPred		0.82		Loss of stability (P = 0.0647);Loss of stability (P = 0.0647);
MVP		0.70
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.72
gMVP		0.64

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: rs1298660906; hg19: chr11-119210070;