chr11-47590140-C-T

Variant names:

• chr11-47590140-C-T
• rs2097274419
• NM_031909.3:c.671G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_031909.3(C1QTNF4):​c.671G>A​(p.Arg224His) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: C1QTNF4 NM_031909.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.96

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C1QTNF4	NM_031909.3	c.671G>A	p.Arg224His	missense_variant	Exon 2 of 2	ENST00000302514.4	NP_114115.2
C1QTNF4	XM_017017166.2	c.671G>A	p.Arg224His	missense_variant	Exon 3 of 3		XP_016872655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C1QTNF4	ENST00000302514.4	c.671G>A	p.Arg224His	missense_variant	Exon 2 of 2	1	NM_031909.3	ENSP00000302274.3
C1QTNF4	ENST00000530097.1	c.301-89G>A		intron_variant	Intron 1 of 1	3		ENSP00000434548.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457170 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725064

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: 0.0000195

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.671G>A (p.R224H) alteration is located in exon 2 (coding exon 1) of the C1QTNF4 gene. This alteration results from a G to A substitution at nucleotide position 671, causing the arginine (R) at amino acid position 224 to be replaced by a histidine (H). 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	0.20
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.2	L
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.28	N
REVEL	Uncertain	0.40
Sift	Benign	0.46	T
Sift4G	Benign	0.57	T
Polyphen		0.73	P
Vest4		0.79
MutPred		0.62		Loss of methylation at R224 (P = 0.027);
MVP		0.84
ClinPred		0.89	D
GERP RS		4.3
Varity_R		0.094
gMVP		0.60

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

Other links and lift over

dbSNP: rs2097274419; hg19: chr11-47611692;