11-119339410-T-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM1PP2BP4BS2_Supporting

The NM_001278431.2(C1QTNF5):c.653A>T(p.Tyr218Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,236 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

C1QTNF5
NM_001278431.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.02

Publications

0 publications found

Variant links:

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]

C1QTNF5 links:

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

MFRP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM1

In a domain C1q (size 139) in uniprot entity C1QT5_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_001278431.2

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.27803195).

BS2

High AC in GnomAdExome4 at 11 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
C1QTNF5	NM_001278431.2 link	c.653A>T	p.Tyr218Phe	missense_variant	Exon 3 of 3	ENST00000528368.3	NP_001265360.1	Q9BXJ0A0A024R3F8
MFRP	NM_031433.4 link	c.*1549A>T		3_prime_UTR_variant	Exon 15 of 15	ENST00000619721.6	NP_113621.1	Q9BY79-1
C1QTNF5	NM_015645.5 link	c.653A>T	p.Tyr218Phe	missense_variant	Exon 15 of 15		NP_056460.1	Q9BXJ0A0A024R3F8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
C1QTNF5	ENST00000528368.3 link	c.653A>T	p.Tyr218Phe	missense_variant	Exon 3 of 3	1	NM_001278431.2	ENSP00000431140.1	Q9BXJ0
C1QTNF5	ENST00000530681.2 link	c.653A>T	p.Tyr218Phe	missense_variant	Exon 2 of 2	1		ENSP00000456533.2	Q9BXJ0
MFRP	ENST00000619721.6 link	c.*1549A>T		3_prime_UTR_variant	Exon 15 of 15	1	NM_031433.4	ENSP00000481824.1	Q9BY79-1
C1QTNF5	ENST00000525657.2 link	n.543A>T		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152036

Hom.:

Cov.:

show subpopulations

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:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000202

AC:

AN:

247982

AF XY:

0.0000372

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1461200

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726802

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.000128

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111518

Other (OTH)

AF:

0.00

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152036

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74258

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41418

American (AMR)

AF:

0.00

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.000208

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67988

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Oct 13, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 218 of the C1QTNF5 protein (p.Tyr218Phe). This variant is present in population databases (rs758015507, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with C1QTNF5-related conditions. ClinVar contains an entry for this variant (Variation ID: 1008550). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.36

T;T

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.84

.;T

M_CAP

Benign

0.066

MetaRNN

Benign

0.28

T;T

MetaSVM

Benign

-0.43

MutationAssessor

Benign

1.6

L;L

PhyloP100

3.0

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-1.7

N;.

REVEL

Uncertain

0.46

Sift

Benign

0.18

T;.

Sift4G

Benign

0.32

T;T

Vest4

0.38

MutPred

0.66

Loss of catalytic residue at I217 (P = 0.0457);Loss of catalytic residue at I217 (P = 0.0457);

MVP

0.50

ClinPred

0.36

GERP RS

4.4

Varity_R

0.51

gMVP

0.44

Mutation Taster

=61/39

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

11-119339410-T-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over