Genetic Variant C1QTNF4:p.Phe231Val (chr11-47590120-A-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_031909.3(C1QTNF4):c.691T>G(p.Phe231Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000277 in 1,611,206 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00029 ( 1 hom. )

Consequence

C1QTNF4
NM_031909.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.10

Variant links:

Genes affected

C1QTNF4 (HGNC:14346): (C1q and TNF related 4) Predicted to enable cytokine activity. Involved in positive regulation of cytokine production and positive regulation of signal transduction. Located in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

C1QTNF4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.91

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C1QTNF4	NM_031909.3 link	c.691T>G	p.Phe231Val	missense_variant	Exon 2 of 2	ENST00000302514.4	NP_114115.2	Q9BXJ3A0A3B0J0L9
C1QTNF4	XM_017017166.2 link	c.691T>G	p.Phe231Val	missense_variant	Exon 3 of 3		XP_016872655.1	Q9BXJ3A0A3B0J0L9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C1QTNF4	ENST00000302514.4 link	c.691T>G	p.Phe231Val	missense_variant	Exon 2 of 2	1	NM_031909.3	ENSP00000302274.3		Q9BXJ3
C1QTNF4	ENST00000530097.1 link	c.301-69T>G		intron_variant	Intron 1 of 1	3		ENSP00000434548.1		E9PPZ5

Frequencies

GnomAD3 genomes

AF:

0.000198

AC:

AN:

151798

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000162

AC:

AN:

240552

Hom.:

AF XY:

0.000174

AC XY:

AN XY:

132132

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:

0.000347

Gnomad OTH exome

AF:

0.000340

GnomAD4 exome

AF:

0.000285

AC:

416

AN:

1459408

Hom.:

Cov.:

AF XY:

0.000285

AC XY:

207

AN XY:

726150

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.000364

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000198

AC:

AN:

151798

Hom.:

Cov.:

AF XY:

0.000189

AC XY:

AN XY:

74134

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000280

Hom.:

Bravo

AF:

0.000166

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000232

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.691T>G (p.F231V) alteration is located in exon 2 (coding exon 1) of the C1QTNF4 gene. This alteration results from a T to G substitution at nucleotide position 691, causing the phenylalanine (F) at amino acid position 231 to be replaced by a valine (V). 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

Pathogenic

0.85

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.71

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.97

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.91

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

3.9

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-5.0

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.036

Polyphen

0.99

Vest4

0.87

MVP

0.94

ClinPred

0.78

GERP RS

4.3

Varity_R

0.83

gMVP

0.96

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