14-24631153-C-T

Variant summary

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

The NM_004131.6(GZMB):c.662G>A(p.Arg221Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,612,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: GZMB NM_004131.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -11.6

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=0.035570055).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GZMB	NM_004131.6	c.662G>A	p.Arg221Gln	missense_variant	5/5	ENST00000216341.9
GZMB	NM_001346011.2	c.626G>A	p.Arg209Gln	missense_variant	5/5
GZMB	NR_144343.2	n.556G>A		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GZMB	ENST00000216341.9	c.662G>A	p.Arg221Gln	missense_variant	5/5	1	NM_004131.6	P2
	ENST00000555300.1	n.177+8027C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000835 AC: 21 AN: 251386 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135864

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000315 AC: 46 AN: 1460682 Hom.: 0 Cov.: 30 AF XY: 0.0000303 AC XY: 22 AN XY: 726734

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000318

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74316

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000761 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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

Sep 14, 2023

The c.662G>A (p.R221Q) alteration is located in exon 5 (coding exon 5) of the GZMB gene. This alteration results from a G to A substitution at nucleotide position 662, causing the arginine (R) at amino acid position 221 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	0.12
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	0.0010
Dann	Benign	0.62
Eigen	Benign	-2.9
Eigen_PC	Benign	-3.0
FATHMM_MKL	Benign	0.0055	N
LIST_S2	Benign	0.066	T;T;T;.;T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.036	T;T;T;T;T
MetaSVM	Benign	-0.72	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.92	N;N;.;N;.
REVEL	Uncertain	0.31
Sift	Benign	0.40	T;T;.;T;.
Sift4G	Benign	0.42	T;T;T;T;T
Polyphen		0.024	.;B;.;.;.
Vest4		0.068
MVP		0.57
MPC		0.21
ClinPred		0.32	T
GERP RS		-10
Varity_R		0.11
gMVP		0.26

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: rs763963542; hg19: chr14-25100359; COSMIC: COSV53544040; COSMIC: COSV53544040;