rs193921077

Positions:

• chr19-54821718-G-A
• chr19-54821718-G-C
• chr19-54821718-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_013289.4(KIR3DL1):​c.809G>A​(p.Arg270His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000653 in 1,608,412 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R270S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000093 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000062 (3 hom.)
• Consequence: KIR3DL1 NM_013289.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.842

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.025999784).
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIR3DL1	NM_013289.4	c.809G>A	p.Arg270His	missense_variant	5/9	ENST00000391728.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIR3DL1	ENST00000391728.8	c.809G>A	p.Arg270His	missense_variant	5/9	1	NM_013289.4	P2
KIR3DL1	ENST00000326542.11	c.809G>A	p.Arg270His	missense_variant	5/8	1		A2
KIR3DL1	ENST00000358178.4	c.524G>A	p.Arg175His	missense_variant	4/8	1

Frequencies

GnomAD3 genomes AF: 0.0000926 AC: 14 AN: 151134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000979

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000659

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000634

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000124 AC: 19 AN: 153704 Hom.: 2 AF XY: 0.000168 AC XY: 14 AN XY: 83540

Gnomad AFR exome AF: 0.0000842

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000759

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000683

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000625 AC: 91 AN: 1457164 Hom.: 3 Cov.: 35 AF XY: 0.0000745 AC XY: 54 AN XY: 724914

Gnomad4 AFR exome AF: 0.000210

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.000617

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.0000333

GnomAD4 genome AF: 0.0000926 AC: 14 AN: 151248 Hom.: 0 Cov.: 32 AF XY: 0.0000677 AC XY: 5 AN XY: 73890

Gnomad4 AFR AF: 0.0000977

Gnomad4 AMR AF: 0.0000658

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000634

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000907

ExAC AF: 0.000108 AC: 12

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 30, 2022

The c.809G>A (p.R270H) alteration is located in exon 5 (coding exon 5) of the KIR3DL1 gene. This alteration results from a G to A substitution at nucleotide position 809, causing the arginine (R) at amino acid position 270 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Malignant tumor of prostate Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Science for Life laboratory, Karolinska Institutet

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	5.5
DANN	Benign	0.94
DEOGEN2	Benign	0.0019	T;.;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.00012	N
M_CAP	Benign	0.00046	T
MetaRNN	Benign	0.026	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PROVEAN	Benign	-0.82	N;N;N
REVEL	Benign	0.050
Sift	Uncertain	0.0040	D;D;D
Sift4G	Benign	0.46	T;T;T
Polyphen		0.93	P;.;.
Vest4		0.067
MutPred		0.41		Loss of MoRF binding (P = 0.0121);Loss of MoRF binding (P = 0.0121);.;
MVP		0.067
MPC		2.1
ClinPred		0.0074	T
GERP RS		-2.9
Varity_R		0.13
gMVP		0.060

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: rs193921077; hg19: chr19-55333173; COSMIC: COSV58487843;