NM_014358.4:c.499G>A

Variant names:

• chr12-8534799-C-T
• rs756443256
• NM_014358.4:c.499G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014358.4(CLEC4E):​c.499G>A​(p.Val167Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,442 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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: 0.0000041 (0 hom.)
• Consequence: CLEC4E NM_014358.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.13
• Publications: 0 publications found

Genes affected

CLEC4E (HGNC:14555): (C-type lectin domain family 4 member E) This gene encodes a member of the C-type lectin/C-type lectin-like domain (CTL/CTLD) superfamily. Members of this family share a common protein fold and have diverse functions, such as cell adhesion, cell-cell signalling, glycoprotein turnover, and roles in inflammation and immune response. The encoded type II transmembrane protein is a downstream target of CCAAT/enhancer binding protein (C/EBP), beta (CEBPB) and may play a role in inflammation. Alternative splice variants have been described but their full-length sequence has not been determined. This gene is closely linked to other CTL/CTLD superfamily members on chromosome 12p13 in the natural killer gene complex region. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03146541).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014358.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLEC4E	NM_014358.4	MANE Select	c.499G>A	p.Val167Ile	missense	Exon 6 of 6	NP_055173.1	Q9ULY5
	CLEC4E	NM_001410969.1		c.364G>A	p.Val122Ile	missense	Exon 5 of 5	NP_001397898.1	F5H5X7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLEC4E	ENST00000299663.8	TSL:1 MANE Select	c.499G>A	p.Val167Ile	missense	Exon 6 of 6	ENSP00000299663.3	Q9ULY5
	CLEC4E	ENST00000545274.5	TSL:3	c.364G>A	p.Val122Ile	missense	Exon 5 of 5	ENSP00000443034.1	F5H5X7
	CLEC4E	ENST00000537698.1	TSL:3	c.200G>A	p.Cys67Tyr	missense	Exon 3 of 3	ENSP00000443328.1	H0YGH9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000201 AC: 5 AN: 249340 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000146

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: 0.00000411 AC: 6 AN: 1460442 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726508

African (AFR) AF: 0.00 AC: 0 AN: 33376

American (AMR) AF: 0.000135 AC: 6 AN: 44386

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26046

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 85944

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111532

Other (OTH) AF: 0.00 AC: 0 AN: 60334

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	2.0
DANN	Benign	0.90
DEOGEN2	Benign	0.062	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.081	T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.29	N
PhyloP100		-1.1
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.035
Sift	Benign	0.18	T
Sift4G	Benign	0.18	T
Polyphen		0.0	B
Vest4		0.058
MutPred		0.34		Gain of solvent accessibility (P = 0.3418)
MVP		0.17
MPC		0.054
ClinPred		0.017	T
GERP RS		-1.0
Varity_R		0.12
gMVP		0.077
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs756443256; hg19: chr12-8687395;