19-54819844-G-A

Position:

• chr19-54819844-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_013289.4(KIR3DL1):​c.487G>A​(p.Asp163Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00655 in 1,611,838 control chromosomes in the GnomAD database, including 175 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0050 (11 hom., cov: 33)
  • Exomes 𝑓: 0.0067 (164 hom.)
• Consequence: KIR3DL1 NM_013289.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.39

Genes affected

KIR3DL1 (HGNC:6338): (killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1) 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0059251487).
• BP6: Variant 19-54819844-G-A is Benign according to our data. Variant chr19-54819844-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2650484.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-54819844-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIR3DL1	NM_013289.4	c.487G>A	p.Asp163Asn	missense_variant	4/9	ENST00000391728.8	NP_037421.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIR3DL1	ENST00000391728.8	c.487G>A	p.Asp163Asn	missense_variant	4/9	1	NM_013289.4	ENSP00000375608	P2
KIR3DL1	ENST00000326542.11	c.487G>A	p.Asp163Asn	missense_variant	4/8	1		ENSP00000326868	A2
KIR3DL1	ENST00000358178.4	c.202G>A	p.Asp68Asn	missense_variant	3/8	1		ENSP00000350901

Frequencies

GnomAD3 genomes AF: 0.00501 AC: 758 AN: 151430 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.00151

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.00480

Gnomad ASJ AF: 0.00232

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000842

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00775

Gnomad OTH AF: 0.00480

GnomAD4 exome AF: 0.00671 AC: 9804 AN: 1460294 Hom.: 164 Cov.: 34 AF XY: 0.00630 AC XY: 4574 AN XY: 726446

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00333

Gnomad4 ASJ exome AF: 0.00262

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00168

Gnomad4 FIN exome AF: 0.000656

Gnomad4 NFE exome AF: 0.00811

Gnomad4 OTH exome AF: 0.00591

GnomAD4 genome AF: 0.00500 AC: 758 AN: 151544 Hom.: 11 Cov.: 33 AF XY: 0.00460 AC XY: 341 AN XY: 74052

Gnomad4 AFR AF: 0.00151

Gnomad4 AMR AF: 0.00479

Gnomad4 ASJ AF: 0.00232

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000842

Gnomad4 FIN AF: 0.000378

Gnomad4 NFE AF: 0.00776

Gnomad4 OTH AF: 0.00475

Alfa AF: 0.00108 Hom.: 0

Bravo AF: 0.00563

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2022

KIR3DL1: BP4, BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.083
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0027	T;.;.
Eigen	Benign	-0.80
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0051	N
M_CAP	Benign	0.00091	T
MetaRNN	Benign	0.0059	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.011
Sift	Uncertain	0.0010	D;D;D
Sift4G	Benign	0.52	T;T;T
Polyphen		0.055	B;.;.
Vest4		0.077
MutPred		0.26		Loss of ubiquitination at K162 (P = 0.0464);Loss of ubiquitination at K162 (P = 0.0464);.;
MVP		0.18
MPC		0.41
ClinPred		0.44	T
GERP RS		0.29
Varity_R		0.35
gMVP		0.016

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

Publications

LitVar

Other links and lift over

dbSNP: rs62124101; hg19: chr19-55331299;