chr19-54739530-T-G

Position:

• chr19-54739530-T-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000342376.4(KIR2DL3):​c.58T>G​(p.Trp20Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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: 𝑓 0.0081 (0 hom., cov: 35)
  • Exomes 𝑓: 0.0033 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KIR2DL3 ENST00000342376.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0160

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010359317).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIR2DL3	NM_015868.3	c.58T>G	p.Trp20Gly	missense_variant	2/8	ENST00000342376.4	NP_056952.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIR2DL3	ENST00000342376.4	c.58T>G	p.Trp20Gly	missense_variant	2/8	1	NM_015868.3	ENSP00000342215	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1224 AN: 150808 Hom.: 0 Cov.: 35 FAILED QC

Gnomad AFR AF: 0.00155

Gnomad AMI AF: 0.00998

Gnomad AMR AF: 0.0110

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00457

Gnomad FIN AF: 0.0165

Gnomad MID AF: 0.0194

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.00678

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00327 AC: 4659 AN: 1426012 Hom.: 0 Cov.: 73 AF XY: 0.00331 AC XY: 2346 AN XY: 709344

Gnomad4 AFR exome AF: 0.00117

Gnomad4 AMR exome AF: 0.00288

Gnomad4 ASJ exome AF: 0.00865

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00354

Gnomad4 FIN exome AF: 0.00788

Gnomad4 NFE exome AF: 0.00298

Gnomad4 OTH exome AF: 0.00448

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00812 AC: 1226 AN: 150930 Hom.: 0 Cov.: 35 AF XY: 0.00892 AC XY: 658 AN XY: 73756

Gnomad4 AFR AF: 0.00157

Gnomad4 AMR AF: 0.0110

Gnomad4 ASJ AF: 0.0173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00478

Gnomad4 FIN AF: 0.0165

Gnomad4 NFE AF: 0.0106

Gnomad4 OTH AF: 0.00670

Alfa AF: 0.00777 Hom.: 0

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 01, 2021

The c.58T>G (p.W20G) alteration is located in exon 2 (coding exon 2) of the KIR2DL3 gene. This alteration results from a T to G substitution at nucleotide position 58, causing the tryptophan (W) at amino acid position 20 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	0.087
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	14
DANN	Benign	0.59
DEOGEN2	Benign	0.026	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0096	N
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	N;N;N;N;N;N
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.11
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.048	D
Polyphen		0.0	B
Vest4		0.20
MutPred		0.44		Gain of disorder (P = 0.002);
MVP		0.35
MPC		4.4
ClinPred		0.16	T
GERP RS		0.42
Varity_R		0.19
gMVP		0.10

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs376053624; hg19: chr19-55250976;