11-119339493-CGA-AAG

Variant names:

• chr11-119339493-CGA-AAG
• NM_001278431.2:c.568_570delTCGinsCTT
• C1QTNF5 p.Ser190Leu

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM5 PP2

The NM_001278431.2(C1QTNF5):​c.568_570delTCGinsCTT​(p.Ser190Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. 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: 5.78
• Publications: 0 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, Orphanet, G2P
• 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, 8 uncertain in NM_001278431.2
• 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, inherited retinal dystrophy.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1QTNF5	NM_001278431.2	MANE Select	c.568_570delTCGinsCTT	p.Ser190Leu	missense	N/A	NP_001265360.1	Q9BXJ0
	MFRP	NM_031433.4	MANE Select	c.*1464_*1466delTCGinsCTT		3_prime_UTR	Exon 15 of 15	NP_113621.1	Q9BY79-1
	C1QTNF5	NM_015645.5		c.568_570delTCGinsCTT	p.Ser190Leu	missense	N/A	NP_056460.1	Q9BXJ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1QTNF5	ENST00000528368.3	TSL:1 MANE Select	c.568_570delTCGinsCTT	p.Ser190Leu	missense	N/A	ENSP00000431140.1	Q9BXJ0
	C1QTNF5	ENST00000530681.2	TSL:1	c.568_570delTCGinsCTT	p.Ser190Leu	missense	N/A	ENSP00000456533.2	Q9BXJ0
	MFRP	ENST00000619721.6	TSL:1 MANE Select	c.*1464_*1466delTCGinsCTT		3_prime_UTR	Exon 15 of 15	ENSP00000481824.1	Q9BY79-1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.8

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr11-119210203;