19-54818402-A-G

Position:

chr19-54818402-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_013289.4(KIR3DL1):c.158A>G(p.His53Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,606,980 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000088 ( 0 hom., cov: 26)

Exomes 𝑓: 0.00011 ( 3 hom. )

Consequence

KIR3DL1
NM_013289.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -5.54

Variant links:

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]

KIR3DL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIR3DL1	NM_013289.4 link	c.158A>G	p.His53Arg	missense_variant	3/9		NP_037421.2	P43629-1Q5UCE2Q8N6C9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Protein	UniProt
KIR3DL1	ENST00000391728.8 link	c.158A>G	p.His53Arg	missense_variant	3/9	1	ENSP00000375608.4	P43629-1
KIR3DL1	ENST00000326542.11 link	c.158A>G	p.His53Arg	missense_variant	3/8	1	ENSP00000326868.7	W5QJC1
KIR3DL1	ENST00000358178.4 link	c.70+833A>G		intron_variant		1	ENSP00000350901.4	P43629-2

Frequencies

GnomAD3 genomes

AF:

0.0000881

AC:

AN:

147550

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000674

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000438

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000148

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000112

AC:

AN:

231444

Hom.:

AF XY:

0.000104

AC XY:

AN XY:

124806

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000114

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000207

Gnomad OTH exome

AF:

0.000352

GnomAD4 exome

AF:

0.000107

AC:

156

AN:

1459430

Hom.:

Cov.:

AF XY:

0.000112

AC XY:

AN XY:

726110

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000132

Gnomad4 OTH exome

AF:

0.0000829

GnomAD4 genome

AF:

0.0000881

AC:

AN:

147550

Hom.:

Cov.:

AF XY:

0.0000974

AC XY:

AN XY:

71876

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000674

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000438

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000148

Gnomad4 OTH

AF:

0.00

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000242

AC:

ExAC

AF:

0.000105

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2023

The c.158A>G (p.H53R) alteration is located in exon 3 (coding exon 3) of the KIR3DL1 gene. This alteration results from a A to G substitution at nucleotide position 158, causing the histidine (H) at amino acid position 53 to be replaced by an arginine (R). 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

0.056

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.32

DANN

Benign

0.18

DEOGEN2

Benign

0.00063

T;.

Eigen

Benign

-2.7

Eigen_PC

Benign

-2.7

FATHMM_MKL

Benign

0.00025

M_CAP

Benign

0.00075

MetaRNN

Benign

0.021

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.44

N;.

PROVEAN

Benign

0.67

N;N

REVEL

Benign

0.0090

Sift

Benign

1.0

T;T

Sift4G

Benign

0.68

T;T

Polyphen

0.0

B;.

Vest4

0.055

MVP

0.067

MPC

0.48

ClinPred

0.038

GERP RS

-2.5

Varity_R

0.12

gMVP

0.089

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.37

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.37

Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over