chr14-24632413-G-C

Position:

• chr14-24632413-G-C

Variant summary

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

The NM_004131.6(GZMB):​c.250C>G​(p.Pro84Ala) 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. 15/21 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: GZMB NM_004131.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.36

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 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=0.03841406).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GZMB	NM_004131.6	c.250C>G	p.Pro84Ala	missense_variant	3/5	ENST00000216341.9	NP_004122.2
GZMB	NM_001346011.2	c.214C>G	p.Pro72Ala	missense_variant	3/5		NP_001332940.1
GZMB	NR_144343.2	n.234-295C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GZMB	ENST00000216341.9	c.250C>G	p.Pro84Ala	missense_variant	3/5	1	NM_004131.6	ENSP00000216341	P2
	ENST00000555300.1	n.177+9287G>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

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

Jun 14, 2024

The c.250C>G (p.P84A) alteration is located in exon 3 (coding exon 3) of the GZMB gene. This alteration results from a C to G substitution at nucleotide position 250, causing the proline (P) at amino acid position 84 to be replaced by an alanine (A). 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	0.091
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	2.3
DANN	Benign	0.55
DEOGEN2	Benign	0.21	.;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.15	T;T
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.038	T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.71	.;N
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.18	N;N
REVEL	Benign	0.25
Sift	Benign	0.46	T;T
Sift4G	Benign	0.49	T;T
Polyphen		0.0	.;B
Vest4		0.066
MutPred		0.35		.;Loss of glycosylation at P84 (P = 0.0499);
MVP		0.51
MPC		0.18
ClinPred		0.11	T
GERP RS		-4.2
Varity_R		0.070
gMVP		0.46

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: rs769013244; hg19: chr14-25101619;