19-54817565-C-A

Position:

chr19-54817565-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_013289.4(KIR3DL1):c.66C>A(p.His22Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000729 in 1,509,386 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000071 ( 0 hom., cov: 26)

Exomes 𝑓: 0.0000073 ( 0 hom. )

Consequence

KIR3DL1
NM_013289.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.796

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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.056492478).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIR3DL1	NM_013289.4 linkuse as main transcript	c.66C>A	p.His22Gln	missense_variant	2/9	ENST00000391728.8	NP_037421.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIR3DL1	ENST00000391728.8 linkuse as main transcript	c.66C>A	p.His22Gln	missense_variant	2/9	1	NM_013289.4	ENSP00000375608	P2	P43629-1
KIR3DL1	ENST00000326542.11 linkuse as main transcript	c.66C>A	p.His22Gln	missense_variant	2/8	1		ENSP00000326868	A2
KIR3DL1	ENST00000358178.4 linkuse as main transcript	c.66C>A	p.His22Gln	missense_variant	2/8	1		ENSP00000350901		P43629-2

Frequencies

GnomAD3 genomes

AF:

0.00000705

AC:

AN:

141810

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000705

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000810

AC:

AN:

123506

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67994

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000698

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000731

AC:

AN:

1367576

Hom.:

Cov.:

AF XY:

0.00000585

AC XY:

AN XY:

683382

show subpopulations

Gnomad4 AFR exome

AF:

0.0000375

Gnomad4 AMR exome

AF:

0.000118

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000243

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.60e-7

Gnomad4 OTH exome

AF:

0.0000176

GnomAD4 genome

AF:

0.00000705

AC:

AN:

141810

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

69078

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000705

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000544

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

Dec 16, 2021

The c.66C>A (p.H22Q) alteration is located in exon 2 (coding exon 2) of the KIR3DL1 gene. This alteration results from a C to A substitution at nucleotide position 66, causing the histidine (H) at amino acid position 22 to be replaced by a glutamine (Q). 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

0.10

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.19

DANN

Benign

0.28

DEOGEN2

Benign

0.014

T;.;.

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.00030

M_CAP

Benign

0.0028

MetaRNN

Benign

0.056

T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

0.60

N;.;N

MutationTaster

Benign

1.0

N;N;N;N;N;N

PROVEAN

Benign

-2.3

N;D;D

REVEL

Benign

0.021

Sift

Uncertain

0.0090

D;D;D

Sift4G

Benign

0.62

T;T;T

Polyphen

0.0040

B;.;.

Vest4

0.068

MutPred

0.42

Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);

MVP

0.076

MPC

0.40

ClinPred

0.071

GERP RS

-1.2

Varity_R

0.062

gMVP

0.079

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

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