Genetic Variant CLEC4D:p.Glu109Lys (chr12-8519101-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_080387.5(CLEC4D):c.325G>A(p.Glu109Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,614,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

CLEC4D
NM_080387.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.233

Variant links:

Genes affected

CLEC4D (HGNC:14554): (C-type lectin domain family 4 member D) 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. 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]

CLEC4D links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12096205).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLEC4D	NM_080387.5 link	c.325G>A	p.Glu109Lys	missense_variant	Exon 4 of 6	ENST00000299665.3	NP_525126.2	Q8WXI8
CLEC4D	XM_011520632.3 link	c.325G>A	p.Glu109Lys	missense_variant	Exon 5 of 7		XP_011518934.1	Q8WXI8
CLEC4D	XM_047428771.1 link	c.325G>A	p.Glu109Lys	missense_variant	Exon 4 of 6		XP_047284727.1
CLEC4D	XM_047428772.1 link	c.325G>A	p.Glu109Lys	missense_variant	Exon 4 of 6		XP_047284728.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLEC4D	ENST00000299665.3 link	c.325G>A	p.Glu109Lys	missense_variant	Exon 4 of 6	1	NM_080387.5	ENSP00000299665.2		Q8WXI8
CLEC4D	ENST00000382064.6 link	c.325G>A	p.Glu109Lys	missense_variant	Exon 5 of 6	3		ENSP00000371496.2		A6NHA5

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251446

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135898

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000322

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000387

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000151

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.325G>A (p.E109K) alteration is located in exon 4 (coding exon 4) of the CLEC4D gene. This alteration results from a G to A substitution at nucleotide position 325, causing the glutamic acid (E) at amino acid position 109 to be replaced by a lysine (K). 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

0.14

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.026

.;T

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.52

T;T

M_CAP

Benign

0.0046

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

.;M

PrimateAI

Benign

0.32

PROVEAN

Benign

-2.3

N;N

REVEL

Benign

0.029

Sift

Benign

0.046

D;D

Sift4G

Benign

0.14

T;D

Polyphen

0.094

.;B

Vest4

0.26

MutPred

0.64

Gain of ubiquitination at E109 (P = 0.0109);Gain of ubiquitination at E109 (P = 0.0109);

MVP

0.21

MPC

0.058

ClinPred

0.097

GERP RS

2.5

Varity_R

0.46

gMVP

0.59

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