19-54724501-C-T

Variant names:

• chr19-54724501-C-T
• rs892116481
• NM_153443.5:c.5C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_153443.5(KIR3DL3):​c.5C>T​(p.Ser2Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00017 in 1,613,034 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00019 (1 hom., cov: 30)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: KIR3DL3 NM_153443.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.51
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06390163).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIR3DL3	NM_153443.5	c.5C>T	p.Ser2Leu	missense_variant	Exon 1 of 8	ENST00000291860.2	NP_703144.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIR3DL3	ENST00000291860.2	c.5C>T	p.Ser2Leu	missense_variant	Exon 1 of 8	1	NM_153443.5	ENSP00000291860.1
ENSG00000215765	ENST00000400864.3	n.6C>T		non_coding_transcript_exon_variant	Exon 1 of 6	5

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 151754 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00333

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000168 AC: 245 AN: 1461162 Hom.: 1 Cov.: 30 AF XY: 0.000217 AC XY: 158 AN XY: 726814

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00202 AC: 174 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52718

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.0000486 AC: 54 AN: 1111996

Other (OTH) AF: 0.000215 AC: 13 AN: 60392

GnomAD4 genome AF: 0.000191 AC: 29 AN: 151872 Hom.: 1 Cov.: 30 AF XY: 0.000283 AC XY: 21 AN XY: 74240

African (AFR) AF: 0.0000483 AC: 2 AN: 41404

American (AMR) AF: 0.00 AC: 0 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5136

South Asian (SAS) AF: 0.00333 AC: 16 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67952

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000869

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 11, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5C>T (p.S2L) alteration is located in exon 1 (coding exon 1) of the KIR3DL3 gene. This alteration results from a C to T substitution at nucleotide position 5, causing the serine (S) at amino acid position 2 to be replaced by a leucine (L). 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	0.22
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	4.1
DANN	Benign	0.93
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0042	N
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-0.97	T
PhyloP100		-1.5
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.046
Sift	Benign	0.22	T
Sift4G	Benign	0.19	T
Vest4		0.092
MutPred		0.29		Loss of disorder (P = 0.0079);
MVP		0.25
MPC		1.8
ClinPred		0.067	T
GERP RS		0.15
PromoterAI		0.0026	Neutral
gMVP		0.076
Mutation Taster		=95/5	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: rs892116481; hg19: chr19-55236006; COSMIC: COSV52547526;