19-54741980-G-A

Position:

• chr19-54741980-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000342376.4(KIR2DL3):​c.71G>A​(p.Gly24Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000542 in 1,603,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00054 (0 hom.)
• Consequence: KIR2DL3 ENST00000342376.4 missense, splice_region
• Scores: Splicing: ADA: 0.4003
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.32

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 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=0.2391968).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIR2DL3	NM_015868.3	c.71G>A	p.Gly24Glu	missense_variant, splice_region_variant	3/8	ENST00000342376.4	NP_056952.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIR2DL3	ENST00000342376.4	c.71G>A	p.Gly24Glu	missense_variant, splice_region_variant	3/8	1	NM_015868.3	ENSP00000342215	P1

Frequencies

GnomAD3 genomes AF: 0.000541 AC: 82 AN: 151634 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.00405

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000839

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000457

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00000629 AC: 1 AN: 158934 Hom.: 0 AF XY: 0.0000117 AC XY: 1 AN XY: 85196

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: 0.0000134

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000541 AC: 786 AN: 1451964 Hom.: 0 Cov.: 32 AF XY: 0.000530 AC XY: 383 AN XY: 722672

Gnomad4 AFR exome AF: 0.000483

Gnomad4 AMR exome AF: 0.000986

Gnomad4 ASJ exome AF: 0.00446

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000792

Gnomad4 FIN exome AF: 0.000188

Gnomad4 NFE exome AF: 0.000390

Gnomad4 OTH exome AF: 0.00100

GnomAD4 genome AF: 0.000547 AC: 83 AN: 151752 Hom.: 0 Cov.: 29 AF XY: 0.000526 AC XY: 39 AN XY: 74170

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00125

Gnomad4 ASJ AF: 0.00405

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000839

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000457

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000506 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

Jul 14, 2021

The c.71G>A (p.G24E) alteration is located in exon 3 (coding exon 3) of the KIR2DL3 gene. This alteration results from a G to A substitution at nucleotide position 71, causing the glycine (G) at amino acid position 24 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	Benign	0.17
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.011	N
M_CAP	Benign	0.00057	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	N;N;N;N;N;N
PROVEAN	Pathogenic	-5.8	D
REVEL	Benign	0.020
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.31
MutPred		0.67		Gain of disorder (P = 0.0671);
MVP		0.43
MPC		3.5
ClinPred		0.95	D
GERP RS		1.6
Varity_R		0.22
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.40
dbscSNV1_RF	Benign	0.43
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.29		Position offset: 3
DS_AL_spliceai		0.23		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1375705580; hg19: chr19-55253426;