3-45026426-G-A

Position:

• chr3-45026426-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_003278.3(CLEC3B):​c.64G>A​(p.Glu22Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 0.0000075 (0 hom.)
• Consequence: CLEC3B NM_003278.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.10

Genes affected

CLEC3B (HGNC:11891): (C-type lectin domain family 3 member B) Enables calcium ion binding activity; heparin binding activity; and kringle domain binding activity. Involved in bone mineralization and cellular response to transforming growth factor beta stimulus. Located in cytoplasm; extracellular space; and granular component. Part of collagen-containing extracellular matrix. Implicated in osteoarthritis. [provided by Alliance of Genome Resources, Apr 2022]

EXOSC7 (HGNC:28112): (exosome component 7) Predicted to enable 3'-5'-exoribonuclease activity and RNA binding activity. Predicted to be involved in RNA metabolic process. Part of exosome (RNase complex). [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18010554).
• BS2: High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLEC3B	NM_003278.3	c.64G>A	p.Glu22Lys	missense_variant	1/3	ENST00000296130.5	NP_003269.2
CLEC3B	XM_017007116.2	c.64G>A	p.Glu22Lys	missense_variant	1/2		XP_016862605.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLEC3B	ENST00000296130.5	c.64G>A	p.Glu22Lys	missense_variant	1/3	1	NM_003278.3	ENSP00000296130	P1
EXOSC7	ENST00000481405.1	n.226-9098G>A		intron_variant, non_coding_transcript_variant		3
CLEC3B	ENST00000490386.1	n.62-4401G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727240

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2022

The c.64G>A (p.E22K) alteration is located in exon 1 (coding exon 1) of the CLEC3B gene. This alteration results from a G to A substitution at nucleotide position 64, causing the glutamic acid (E) at amino acid position 22 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	0.095
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.052
Sift	Benign	0.34	T
Sift4G	Benign	0.80	T
Polyphen		0.49	P
Vest4		0.25
MutPred		0.40		Gain of methylation at E22 (P = 0.0059);
MVP		0.37
MPC		1.2
ClinPred		0.46	T
GERP RS		3.0
Varity_R		0.083
gMVP		0.34

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: rs1455334649; hg19: chr3-45067918;