Genetic Variant C1QTNF1:p.Thr125Ile (chr17-79047616-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_030968.5(C1QTNF1):c.374C>T(p.Thr125Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000418 in 1,434,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

C1QTNF1
NM_030968.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.388

Variant links:

Genes affected

C1QTNF1 (HGNC:14324): (C1q and TNF related 1) Enables collagen binding activity. Involved in several processes, including negative regulation of platelet aggregation; positive regulation of aldosterone secretion; and positive regulation of cytosolic calcium ion concentration. Located in extracellular space. Is integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

C1QTNF1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04456064).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C1QTNF1	NM_030968.5 link	c.374C>T	p.Thr125Ile	missense_variant	Exon 4 of 4	ENST00000579760.6	NP_112230.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C1QTNF1	ENST00000579760.6 link	c.374C>T	p.Thr125Ile	missense_variant	Exon 4 of 4	1	NM_030968.5	ENSP00000463922.1		Q9BXJ1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000429

AC:

AN:

233116

Hom.:

AF XY:

0.00

AC XY:

AN XY:

125880

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000938

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000418

AC:

AN:

1434268

Hom.:

Cov.:

AF XY:

0.00000563

AC XY:

AN XY:

710468

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000365

Gnomad4 OTH exome

AF:

0.0000339

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 21, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.374C>T (p.T125I) alteration is located in exon 4 (coding exon 3) of the C1QTNF1 gene. This alteration results from a C to T substitution at nucleotide position 374, causing the threonine (T) at amino acid position 125 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.072

BayesDel_noAF

Benign

-0.34

CADD

Benign

2.1

DANN

Benign

0.91

DEOGEN2

Benign

0.030

T;T;T;T;T;T;T;T;T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.36

.;T;.;.;.;T;.;.;.;.

M_CAP

Benign

0.025

MetaRNN

Benign

0.045

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.36

MutationAssessor

Benign

0.34

.;N;N;N;N;.;N;N;N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.3

.;.;.;.;N;N;.;.;.;.

REVEL

Benign

0.27

Sift

Benign

0.28

.;.;.;.;T;T;.;.;.;.

Sift4G

Benign

0.21

T;T;T;T;T;T;T;T;T;T

Polyphen

0.0010

.;B;B;B;B;.;B;B;B;B

Vest4

0.11

MutPred

0.31

.;Loss of phosphorylation at T125 (P = 0.0175);Loss of phosphorylation at T125 (P = 0.0175);Loss of phosphorylation at T125 (P = 0.0175);Loss of phosphorylation at T125 (P = 0.0175);.;Loss of phosphorylation at T125 (P = 0.0175);Loss of phosphorylation at T125 (P = 0.0175);Loss of phosphorylation at T125 (P = 0.0175);Loss of phosphorylation at T125 (P = 0.0175);

MVP

0.59

MPC

0.31

ClinPred

0.033

GERP RS

-5.7

Varity_R

0.036

gMVP

0.10

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over