19-54819972-G-C

Position:

• chr19-54819972-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000391728.8(KIR3DL1):​c.615G>C​(p.Gln205His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. Q205E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KIR3DL1 ENST00000391728.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.715

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 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=0.052768975).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIR3DL1	NM_013289.4	c.615G>C	p.Gln205His	missense_variant	4/9		NP_037421.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIR3DL1	ENST00000391728.8	c.615G>C	p.Gln205His	missense_variant	4/9	1		ENSP00000375608.4
KIR3DL1	ENST00000326542.11	c.615G>C	p.Gln205His	missense_variant	4/8	1		ENSP00000326868.7
KIR3DL1	ENST00000358178.4	c.330G>C	p.Gln110His	missense_variant	3/8	1		ENSP00000350901.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2024

The c.615G>C (p.Q205H) alteration is located in exon 4 (coding exon 4) of the KIR3DL1 gene. This alteration results from a G to C substitution at nucleotide position 615, causing the glutamine (Q) at amino acid position 205 to be replaced by a histidine (H). 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	0.28
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	12
DANN	Benign	0.97
DEOGEN2	Benign	0.0017	T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.013	N
M_CAP	Benign	0.00075	T
MetaRNN	Benign	0.053	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.1	L;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.066
Sift	Benign	0.048	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		0.14	B;.;.
Vest4		0.049
MutPred		0.22		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;
MVP		0.076
MPC		0.37
ClinPred		0.12	T
GERP RS		-1.2
Varity_R		0.22
gMVP		0.058

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1471729756; hg19: chr19-55331427;