19-54727901-G-A

Position:

• chr19-54727901-G-A

Variant summary

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

The NM_153443.5(KIR3DL3):​c.646G>A​(p.Val216Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000684 in 1,608,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: KIR3DL3 NM_153443.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.51

Genes affected

KIR3DL3 (HGNC:16312): (killer cell immunoglobulin like receptor, three 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. This gene is one of the "framework" loci that is present on all haplotypes. [provided by RefSeq, Jul 2008]

ENSG00000215765 (HGNC:):

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=0.073512495).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIR3DL3	NM_153443.5	c.646G>A	p.Val216Met	missense_variant	4/8	ENST00000291860.2	NP_703144.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIR3DL3	ENST00000291860.2	c.646G>A	p.Val216Met	missense_variant	4/8	1	NM_153443.5	ENSP00000291860.1
ENSG00000215765	ENST00000400864.3	n.35+3371G>A		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152134 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000294

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000175 AC: 1 AN: 57028 Hom.: 0 AF XY: 0.0000322 AC XY: 1 AN XY: 31092

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: 0.0000317

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000474 AC: 69 AN: 1456078 Hom.: 0 Cov.: 34 AF XY: 0.0000497 AC XY: 36 AN XY: 723658

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.000135

Gnomad4 ASJ exome AF: 0.0000388

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000467

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000902

Gnomad4 OTH exome AF: 0.000183

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152134 Hom.: 0 Cov.: 30 AF XY: 0.000296 AC XY: 22 AN XY: 74316

Gnomad4 AFR AF: 0.000845

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000230

ExAC AF: 0.0000355 AC: 3

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

Apr 22, 2022

The c.646G>A (p.V216M) alteration is located in exon 4 (coding exon 4) of the KIR3DL3 gene. This alteration results from a G to A substitution at nucleotide position 646, causing the valine (V) at amino acid position 216 to be replaced by a methionine (M). 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	0.098
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.7
DANN	Benign	0.72
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0014	N
M_CAP	Benign	0.0010	T
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-0.99	T
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.070
Sift	Uncertain	0.023	D
Sift4G	Benign	0.13	T
Vest4		0.084
MutPred		0.54		Loss of catalytic residue at V216 (P = 0.0488);
MVP		0.068
MPC		1.9
ClinPred		0.096	T
GERP RS		-2.8
gMVP		0.031

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: rs757092065; hg19: chr19-55239367;