rs1257648865

Variant names:

• chr19-54726328-A-C
• rs1257648865
• NM_153443.5:c.346A>C

Your query was ambiguous. Multiple possible variants found:

• chr19-54726328-A-C
• chr19-54726328-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_153443.5(KIR3DL3):​c.346A>C​(p.Met116Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,636 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M116V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: KIR3DL3 NM_153443.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.941
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07492173).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIR3DL3	NM_153443.5	c.346A>C	p.Met116Leu	missense_variant	Exon 3 of 8	ENST00000291860.2	NP_703144.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIR3DL3	ENST00000291860.2	c.346A>C	p.Met116Leu	missense_variant	Exon 3 of 8	1	NM_153443.5	ENSP00000291860.1
ENSG00000215765	ENST00000400864.3	n.35+1798A>C		intron_variant	Intron 1 of 5	5

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461636 Hom.: 0 Cov.: 37 AF XY: 0.00000413 AC XY: 3 AN XY: 727148

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53236

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111970

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.80
DANN	Benign	0.55
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0052	N
M_CAP	Benign	0.00091	T
MetaRNN	Benign	0.075	T
MetaSVM	Benign	-0.98	T
PhyloP100		-0.94
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.020
Sift	Uncertain	0.0040	D
Sift4G	Benign	1.0	T
Vest4		0.087
MutPred		0.36		Loss of sheet (P = 0.1158);
MVP		0.043
MPC		1.7
ClinPred		0.61	D
GERP RS		-3.6
gMVP		0.053
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs1257648865; hg19: chr19-55237794;