rs121908190

Variant names:

• chr11-119345516-A-G
• rs121908190
• NM_031433.4:c.545T>C

Your query was ambiguous. Multiple possible variants found:

• chr11-119345516-A-G
• chr11-119345516-A-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_031433.4(MFRP):​c.545T>C​(p.Ile182Thr) 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. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I182M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MFRP NM_031433.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.94
• Publications: 5 publications found

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]

C1QTNF5 Gene-Disease associations (from GenCC):

• late-onset retinal degeneration

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 11-119345516-A-G is Pathogenic according to our data. Variant chr11-119345516-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 4477.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MFRP	NM_031433.4	c.545T>C	p.Ile182Thr	missense_variant	Exon 5 of 15	ENST00000619721.6	NP_113621.1
C1QTNF5	NM_015645.5	c.-2092T>C		5_prime_UTR_variant	Exon 5 of 15		NP_056460.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MFRP	ENST00000619721.6	c.545T>C	p.Ile182Thr	missense_variant	Exon 5 of 15	1	NM_031433.4	ENSP00000481824.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00110 Hom.: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Nanophthalmos 2 Pathogenic:1

Jul 05, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Pathogenic	3.9	H;H
PhyloP100		4.9
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.5	.;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0010	.;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		0.86	P;.
Vest4		0.82
MutPred		0.93		Loss of stability (P = 0.039);Loss of stability (P = 0.039);
MVP		0.40
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.42
gMVP		0.73
Mutation Taster		=9/91	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs121908190; hg19: chr11-119216226;