14-24631965-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004131.6(GZMB):c.493A>G(p.Met165Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: GZMB NM_004131.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.238

Genes affected

GZMB (HGNC:4709): (granzyme B) This gene encodes a member of the granzyme subfamily of proteins, part of the peptidase S1 family of serine proteases. The encoded preproprotein is secreted by natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) and proteolytically processed to generate the active protease, which induces target cell apoptosis. This protein also processes cytokines and degrades extracellular matrix proteins, and these roles are implicated in chronic inflammation and wound healing. Expression of this gene may be elevated in human patients with cardiac fibrosis. [provided by RefSeq, Sep 2016]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09159973).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GZMB	NM_004131.6	c.493A>G	p.Met165Val	missense_variant	4/5	ENST00000216341.9
GZMB	NM_001346011.2	c.457A>G	p.Met153Val	missense_variant	4/5
GZMB	NR_144343.2	n.387A>G		non_coding_transcript_exon_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GZMB	ENST00000216341.9	c.493A>G	p.Met165Val	missense_variant	4/5	1	NM_004131.6	P2
	ENST00000555300.1	n.177+8839T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152238 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74380

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

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

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

Apr 13, 2022

The c.493A>G (p.M165V) alteration is located in exon 4 (coding exon 4) of the GZMB gene. This alteration results from a A to G substitution at nucleotide position 493, causing the methionine (M) at amino acid position 165 to be replaced by a valine (V). 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	0.19
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	5.7
Dann	Benign	0.32
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.61	T;T;T;.;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.092	T;T;T;T;T
MetaSVM	Benign	-0.77	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.2	N;N;.;N;.
REVEL	Benign	0.27
Sift	Benign	0.064	T;D;.;D;.
Sift4G	Benign	0.16	T;T;T;T;T
Polyphen		0.0020	.;B;.;.;.
Vest4		0.18
MutPred		0.46		.;Loss of catalytic residue at M165 (P = 0.0304);.;.;.;
MVP		0.48
MPC		0.18
ClinPred		0.058	T
GERP RS		0.040
Varity_R		0.16
gMVP		0.54

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: rs1466089628; hg19: chr14-25101171;