chr12-9009020-C-A

Position:

• chr12-9009020-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005810.4(KLRG1):​c.403C>A​(p.Leu135Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: KLRG1 NM_005810.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0160

Genes affected

KLRG1 (HGNC:6380): (killer cell lectin like receptor G1) Natural killer (NK) cells are lymphocytes that can mediate lysis of certain tumor cells and virus-infected cells without previous activation. They can also regulate specific humoral and cell-mediated immunity. The protein encoded by this gene belongs to the killer cell lectin-like receptor (KLR) family, which is a group of transmembrane proteins preferentially expressed in NK cells. Studies in mice suggested that the expression of this gene may be regulated by MHC class I molecules. [provided by RefSeq, Jun 2016]

KLRG1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLRG1	NM_005810.4	c.403C>A	p.Leu135Met	missense_variant	4/5	ENST00000356986.8	NP_005801.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLRG1	ENST00000356986.8	c.403C>A	p.Leu135Met	missense_variant	4/5	1	NM_005810.4	ENSP00000349477.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

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

Dec 21, 2022

The c.403C>A (p.L135M) alteration is located in exon 4 (coding exon 4) of the KLRG1 gene. This alteration results from a C to A substitution at nucleotide position 403, causing the leucine (L) at amino acid position 135 to be replaced by a methionine (M). 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	0.34
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	.;.;T;.
Eigen	Benign	-0.019
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.65	T;T;T;T
M_CAP	Benign	0.0029	T
MetaRNN	Uncertain	0.52	D;D;D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Pathogenic	3.4	.;M;M;.
MutationTaster	Benign	0.90	N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.0	N;N;N;N
REVEL	Benign	0.19
Sift	Uncertain	0.0060	D;D;D;D
Sift4G	Uncertain	0.0080	D;T;T;D
Polyphen		1.0	.;D;D;.
Vest4		0.39, 0.38
MutPred		0.68		.;Gain of catalytic residue at W132 (P = 0);Gain of catalytic residue at W132 (P = 0);.;
MVP		0.44
MPC		0.56
ClinPred		0.92	D
GERP RS		-0.15
Varity_R		0.34
gMVP		0.42

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-9161616;