rs906525288

Variant names:

• chr11-119339494-G-A
• rs906525288
• NM_001278431.2:c.569C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-119339494-G-A
• chr11-119339494-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP2 PP3

The NM_001278431.2(C1QTNF5):​c.569C>T​(p.Ser190Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S190W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: C1QTNF5 NM_001278431.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.50
• Publications: 6 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: Likely_pathogenic. The variant received 8 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, 8 uncertain in NM_001278431.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-119339494-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 438183.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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, 0.838

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.569C>T	p.Ser190Leu	missense	Exon 3 of 3	NP_001265360.1
	MFRP	NM_031433.4	MANE Select	c.*1465C>T		3_prime_UTR	Exon 15 of 15	NP_113621.1
	C1QTNF5	NM_015645.5		c.569C>T	p.Ser190Leu	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.569C>T	p.Ser190Leu	missense	Exon 3 of 3	ENSP00000431140.1
	C1QTNF5	ENST00000530681.2	TSL:1	c.569C>T	p.Ser190Leu	missense	Exon 2 of 2	ENSP00000456533.2
	MFRP	ENST00000619721.6	TSL:1 MANE Select	c.*1465C>T		3_prime_UTR	Exon 15 of 15	ENSP00000481824.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		5.5
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.4	N
REVEL	Pathogenic	0.68
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.0060	D
Vest4		0.74
MutPred		0.75		Loss of disorder (P = 0.0043)
MVP		0.79
ClinPred		0.97	D
GERP RS		4.4
Varity_R		0.46
gMVP		0.73
Mutation Taster		=62/38	polymorphism

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: rs906525288; hg19: chr11-119210204; COSMIC: COSV60990858; COSMIC: COSV60990858;