Variant 19-54743830-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_015868.3(KIR2DL3):c.406G>A(p.Gly136Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,460,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

KIR2DL3
NM_015868.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.363

Variant links:

Genes affected

KIR2DL3 (HGNC:6331): (killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3) Killer cell immunoglobulin-like receptors (KIRs) are transmembrane glycoproteins expressed by natural killer cells and subsets of T cells. The KIR genes are polymorphic and highly homologous and they are found in a cluster on chromosome 19q13.4 within the 1 Mb leukocyte receptor complex (LRC). The gene content of the KIR gene cluster varies among haplotypes, although several "framework" genes are found in all haplotypes (KIR3DL3, KIR3DP1, KIR3DL4, KIR3DL2). The KIR proteins are classified by the number of extracellular immunoglobulin domains (2D or 3D) and by whether they have a long (L) or short (S) cytoplasmic domain. KIR proteins with the long cytoplasmic domain transduce inhibitory signals upon ligand binding via an immune tyrosine-based inhibitory motif (ITIM), while KIR proteins with the short cytoplasmic domain lack the ITIM motif and instead associate with the TYRO protein tyrosine kinase binding protein to transduce activating signals. The ligands for several KIR proteins are subsets of HLA class I molecules; thus, KIR proteins are thought to play an important role in regulation of the immune response. [provided by RefSeq, Jul 2008]

KIR2DL3 links:

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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=0.19804987).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIR2DL3	NM_015868.3 linkuse as main transcript	c.406G>A	p.Gly136Ser	missense_variant	4/8	ENST00000342376.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIR2DL3	ENST00000342376.4 linkuse as main transcript	c.406G>A	p.Gly136Ser	missense_variant	4/8	1	NM_015868.3	P1	P43628-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1460308

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726494

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

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:

0.00000900

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Mar 14, 2023

The c.406G>A (p.G136S) alteration is located in exon 4 (coding exon 4) of the KIR2DL3 gene. This alteration results from a G to A substitution at nucleotide position 406, causing the glycine (G) at amino acid position 136 to be replaced by a serine (S). 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

0.11

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.73

CADD

Benign

6.9

DANN

Uncertain

0.99

DEOGEN2

Benign

0.027

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.0062

M_CAP

Benign

0.0015

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.87

MutationAssessor

Benign

0.75

MutationTaster

Benign

1.0

N;N;N;N;N;N

PROVEAN

Uncertain

-3.6

REVEL

Benign

0.029

Sift

Uncertain

0.012

Sift4G

Benign

0.092

Polyphen

0.66

Vest4

0.15

MutPred

0.38

Gain of glycosylation at G136 (P = 0.0066);

MVP

0.30

MPC

3.0

ClinPred

0.29

GERP RS

0.11

Varity_R

0.28

gMVP

0.11

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over