rs730882144

Variant names:

• chr11-119341739-G-A
• rs730882144
• NM_031433.4:c.1549C>T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS2_Supporting

The NM_015645.5(C1QTNF5):​c.-1088C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,613,264 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: C1QTNF5 NM_015645.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 3.53

Genes affected

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]

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• BS2: High AC in GnomAdExome4 at 14 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MFRP	NM_031433.4	c.1549C>T	p.Arg517Trp	missense_variant	Exon 13 of 15	ENST00000619721.6	NP_113621.1
C1QTNF5	NM_015645.5	c.-1088C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 13 of 15		NP_056460.1
C1QTNF5	NM_015645.5	c.-1088C>T		5_prime_UTR_variant	Exon 13 of 15		NP_056460.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MFRP	ENST00000619721.6	c.1549C>T	p.Arg517Trp	missense_variant	Exon 13 of 15	1	NM_031433.4	ENSP00000481824.1
MFRP	ENST00000360167.4	c.1195C>T	p.Arg399Trp	missense_variant	Exon 10 of 10	2		ENSP00000353291.4
MFRP	ENST00000449574.7	c.418C>T	p.Arg140Trp	missense_variant	Exon 4 of 4	5		ENSP00000391664.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000202 AC: 5 AN: 247292 Hom.: 0 AF XY: 0.0000298 AC XY: 4 AN XY: 134452

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461036 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 726804

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152228 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74368

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Isolated microphthalmia 5 Pathogenic:1 Uncertain:1

Mar 14, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.42	T;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Pathogenic	3.6	H;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.2	.;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.028	.;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.25
MutPred		0.70		Loss of catalytic residue at R517 (P = 0.1665);.;
MVP		0.87
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.57
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs730882144; hg19: chr11-119212449;