12-8519045-C-G

Variant names:

• chr12-8519045-C-G
• rs369634533
• NM_080387.5:c.269C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_080387.5(CLEC4D):​c.269C>G​(p.Ala90Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A90T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CLEC4D NM_080387.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0330

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]

ACMG classification

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=0.08562252).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLEC4D	NM_080387.5	c.269C>G	p.Ala90Gly	missense_variant	Exon 4 of 6	ENST00000299665.3	NP_525126.2
CLEC4D	XM_011520632.3	c.269C>G	p.Ala90Gly	missense_variant	Exon 5 of 7		XP_011518934.1
CLEC4D	XM_047428771.1	c.269C>G	p.Ala90Gly	missense_variant	Exon 4 of 6		XP_047284727.1
CLEC4D	XM_047428772.1	c.269C>G	p.Ala90Gly	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	c.269C>G	p.Ala90Gly	missense_variant	Exon 4 of 6	1	NM_080387.5	ENSP00000299665.2
CLEC4D	ENST00000382064.6	c.269C>G	p.Ala90Gly	missense_variant	Exon 5 of 6	3		ENSP00000371496.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461824 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727206

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 04, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.269C>G (p.A90G) alteration is located in exon 4 (coding exon 4) of the CLEC4D gene. This alteration results from a C to G substitution at nucleotide position 269, causing the alanine (A) at amino acid position 90 to be replaced by a glycine (G). 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	0.10
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.0065	.;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.062	T;T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.086	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.8	.;L
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.042
Sift	Benign	0.14	T;T
Sift4G	Benign	0.32	T;T
Polyphen		0.0010	.;B
Vest4		0.28
MutPred		0.53		Loss of stability (P = 0.0527);Loss of stability (P = 0.0527);
MVP		0.15
MPC		0.031
ClinPred		0.064	T
GERP RS		0.47
Varity_R		0.22
gMVP		0.25

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: rs369634533; hg19: chr12-8671641;