3-45035536-G-A

Position:

chr3-45035536-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_003278.3(CLEC3B):c.221G>A(p.Gly74Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000206 in 1,605,140 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: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

CLEC3B
NM_003278.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.41

Variant links:

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]

CLEC3B links:

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]

EXOSC7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.937

BS2

High AC in GnomAdExome4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CLEC3B	NM_003278.3 linkuse as main transcript	c.221G>A	p.Gly74Glu	missense_variant	3/3	ENST00000296130.5	NP_003269.2
CLEC3B	NM_001308394.2 linkuse as main transcript	c.95G>A	p.Gly32Glu	missense_variant	3/3		NP_001295323.1
CLEC3B	XM_017007116.2 linkuse as main transcript	c.122G>A	p.Gly41Glu	missense_variant	2/2		XP_016862605.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
CLEC3B	ENST00000296130.5 linkuse as main transcript	c.221G>A	p.Gly74Glu	missense_variant	3/3	1	NM_003278.3	ENSP00000296130	P1
CLEC3B	ENST00000428034.1 linkuse as main transcript	c.95G>A	p.Gly32Glu	missense_variant	3/3	2		ENSP00000396013
EXOSC7	ENST00000481405.1 linkuse as main transcript	n.238G>A		non_coding_transcript_exon_variant	3/3	3
CLEC3B	ENST00000490386.1 linkuse as main transcript	n.173G>A		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000408

AC:

AN:

245022

Hom.:

AF XY:

0.00000756

AC XY:

AN XY:

132296

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:

0.00000910

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000206

AC:

AN:

1452946

Hom.:

Cov.:

AF XY:

0.0000236

AC XY:

AN XY:

721392

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000271

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000571

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2022

The c.221G>A (p.G74E) alteration is located in exon 3 (coding exon 3) of the CLEC3B gene. This alteration results from a G to A substitution at nucleotide position 221, causing the glycine (G) at amino acid position 74 to be replaced by a glutamic acid (E). 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

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

D;T

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

D;D

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Uncertain

-0.14

MutationAssessor

Uncertain

2.7

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-7.9

D;D

REVEL

Pathogenic

0.65

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0050

D;D

Polyphen

1.0

D;.

Vest4

0.90

MutPred

0.80

Loss of MoRF binding (P = 0.0424);.;

MVP

0.82

MPC

1.9

ClinPred

1.0

GERP RS

4.5

Varity_R

0.98

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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