NM_001278431.2:c.556C>T

Variant names:

• chr11-119339507-G-A
• rs1555036138
• NM_001278431.2:c.556C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1 PM2 PP2 PP5 BP4

The NM_001278431.2(C1QTNF5):​c.556C>T​(p.Pro186Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: C1QTNF5 NM_001278431.2 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.82
• Publications: 1 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001278431.2
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP5: Variant 11-119339507-G-A is Pathogenic according to our data. Variant chr11-119339507-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 438182.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.21386418). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C1QTNF5	NM_001278431.2	c.556C>T	p.Pro186Ser	missense_variant	Exon 3 of 3	ENST00000528368.3	NP_001265360.1
MFRP	NM_031433.4	c.*1452C>T		3_prime_UTR_variant	Exon 15 of 15	ENST00000619721.6	NP_113621.1
C1QTNF5	NM_015645.5	c.556C>T	p.Pro186Ser	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.556C>T	p.Pro186Ser	missense_variant	Exon 3 of 3	1	NM_001278431.2	ENSP00000431140.1
C1QTNF5	ENST00000530681.2	c.556C>T	p.Pro186Ser	missense_variant	Exon 2 of 2	1		ENSP00000456533.2
MFRP	ENST00000619721.6	c.*1452C>T		3_prime_UTR_variant	Exon 15 of 15	1	NM_031433.4	ENSP00000481824.1
C1QTNF5	ENST00000525657.2	n.446C>T		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Retinal dystrophy Pathogenic:1

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.14	T;T
Eigen	Benign	0.044
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.88	.;D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.65	N;N
PhyloP100		3.8
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.35	N;.
REVEL	Benign	0.10
Sift	Benign	0.79	T;.
Sift4G	Benign	0.58	T;T
Vest4		0.38
MutPred		0.29		Loss of glycosylation at P186 (P = 0.0554);Loss of glycosylation at P186 (P = 0.0554);
MVP		0.45
ClinPred		0.44	T
GERP RS		4.4
Varity_R		0.19
gMVP		0.62
Mutation Taster		=77/23	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: rs1555036138; hg19: chr11-119210217;