rs193921051

chr19-54741976-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015868.3(KIR2DL3):c.71-4C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 112,370 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.12 (2 hom., cov: 28)
  • Exomes 𝑓: 0.17 (44 hom.)
  • Failed GnomAD Quality Control
• Consequence: KIR2DL3 NM_015868.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003298
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -1.19

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIR2DL3	NM_015868.3	c.71-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000342376.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIR2DL3	ENST00000342376.4	c.71-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_015868.3	P1

Frequencies

GnomAD3 genomes AF: 0.122 AC: 13673 AN: 112272 Hom.: 2 Cov.: 28

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.0865

Gnomad AMR AF: 0.142

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.0486

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.0958

Gnomad MID AF: 0.183

Gnomad NFE AF: 0.131

Gnomad OTH AF: 0.126

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.169 AC: 189717 AN: 1125568 Hom.: 44 Cov.: 31 AF XY: 0.171 AC XY: 95199 AN XY: 557030

Gnomad4 AFR exome AF: 0.146

Gnomad4 AMR exome AF: 0.156

Gnomad4 ASJ exome AF: 0.224

Gnomad4 EAS exome AF: 0.0461

Gnomad4 SAS exome AF: 0.249

Gnomad4 FIN exome AF: 0.117

Gnomad4 NFE exome AF: 0.170

Gnomad4 OTH exome AF: 0.175

GnomAD4 genome AF: 0.122 AC: 13688 AN: 112370 Hom.: 2 Cov.: 28 AF XY: 0.122 AC XY: 6706 AN XY: 54944

Gnomad4 AFR AF: 0.105

Gnomad4 AMR AF: 0.141

Gnomad4 ASJ AF: 0.178

Gnomad4 EAS AF: 0.0487

Gnomad4 SAS AF: 0.195

Gnomad4 FIN AF: 0.0958

Gnomad4 NFE AF: 0.131

Gnomad4 OTH AF: 0.130

Alfa AF: 0.118 Hom.: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Malignant tumor of prostate Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Science for Life laboratory, Karolinska Institutet

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	0.58
Dann	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000033
dbscSNV1_RF	Benign	0.0
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: rs193921051; hg19: chr19-55253422; COSMIC: COSV60898587;