14-24632954-C-T

Variant names:

• chr14-24632954-C-T
• rs8192917
• NM_004131.6:c.164G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004131.6(GZMB):​c.164G>A​(p.Arg55Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.761 in 1,613,204 control chromosomes in the GnomAD database, including 468,892 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.72 (40116 hom., cov: 31)
  • Exomes 𝑓: 0.76 (428776 hom.)
• Consequence: GZMB NM_004131.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.31

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]

ENSG00000258657 (HGNC:58166):

LOC105370413 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.7180812E-6).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.782 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GZMB	NM_004131.6	c.164G>A	p.Arg55Gln	missense_variant	Exon 2 of 5	ENST00000216341.9	NP_004122.2
GZMB	NM_001346011.2	c.128G>A	p.Arg43Gln	missense_variant	Exon 2 of 5		NP_001332940.1
GZMB	NR_144343.2	n.194G>A		non_coding_transcript_exon_variant	Exon 2 of 4
LOC105370413	XR_007064087.1	n.-148C>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GZMB	ENST00000216341.9	c.164G>A	p.Arg55Gln	missense_variant	Exon 2 of 5	1	NM_004131.6	ENSP00000216341.4

Frequencies

GnomAD3 genomes AF: 0.721 AC: 109568 AN: 151864 Hom.: 40102 Cov.: 31

Gnomad AFR AF: 0.587

Gnomad AMI AF: 0.866

Gnomad AMR AF: 0.794

Gnomad ASJ AF: 0.771

Gnomad EAS AF: 0.731

Gnomad SAS AF: 0.671

Gnomad FIN AF: 0.808

Gnomad MID AF: 0.693

Gnomad NFE AF: 0.772

Gnomad OTH AF: 0.714

GnomAD2 exomes AF: 0.755 AC: 189367 AN: 250770 AF XY: 0.751

Gnomad AFR exome AF: 0.578

Gnomad AMR exome AF: 0.848

Gnomad ASJ exome AF: 0.755

Gnomad EAS exome AF: 0.727

Gnomad FIN exome AF: 0.805

Gnomad NFE exome AF: 0.767

Gnomad OTH exome AF: 0.764

GnomAD4 exome AF: 0.765 AC: 1117266 AN: 1461222 Hom.: 428776 Cov.: 46 AF XY: 0.762 AC XY: 554016 AN XY: 726898

Gnomad4 AFR exome AF: 0.579 AC: 19367 AN: 33466

Gnomad4 AMR exome AF: 0.840 AC: 37542 AN: 44670

Gnomad4 ASJ exome AF: 0.755 AC: 19708 AN: 26102

Gnomad4 EAS exome AF: 0.773 AC: 30685 AN: 39698

Gnomad4 SAS exome AF: 0.684 AC: 58958 AN: 86180

Gnomad4 FIN exome AF: 0.800 AC: 42742 AN: 53408

Gnomad4 NFE exome AF: 0.773 AC: 859251 AN: 1111568

Gnomad4 Remaining exome AF: 0.745 AC: 44993 AN: 60364

GnomAD4 genome AF: 0.721 AC: 109627 AN: 151982 Hom.: 40116 Cov.: 31 AF XY: 0.726 AC XY: 53895 AN XY: 74274

Gnomad4 AFR AF: 0.587 AC: 0.586512 AN: 0.586512

Gnomad4 AMR AF: 0.794 AC: 0.794314 AN: 0.794314

Gnomad4 ASJ AF: 0.771 AC: 0.77147 AN: 0.77147

Gnomad4 EAS AF: 0.731 AC: 0.730814 AN: 0.730814

Gnomad4 SAS AF: 0.671 AC: 0.670676 AN: 0.670676

Gnomad4 FIN AF: 0.808 AC: 0.808418 AN: 0.808418

Gnomad4 NFE AF: 0.772 AC: 0.772354 AN: 0.772354

Gnomad4 OTH AF: 0.709 AC: 0.708807 AN: 0.708807

Alfa AF: 0.750 Hom.: 212107

Bravo AF: 0.716

TwinsUK AF: 0.771 AC: 2859

ALSPAC AF: 0.771 AC: 2971

ESP6500AA AF: 0.595 AC: 2622

ESP6500EA AF: 0.764 AC: 6567

ExAC AF: 0.747 AC: 90659

Asia WGS AF: 0.663 AC: 2304 AN: 3478

EpiCase AF: 0.759

EpiControl AF: 0.752

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	.;T;T;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.75	T;T;.;T;T
MetaRNN	Benign	0.0000017	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.92	.;L;.;.;.
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.7	N;N;N;.;N
REVEL	Benign	0.14
Sift	Benign	0.41	T;T;T;.;T
Sift4G	Benign	0.34	T;T;T;T;T
Polyphen		0.34	.;B;.;.;.
Vest4		0.035
MPC		0.22
ClinPred		0.0064	T
GERP RS		-1.1
Varity_R		0.19
gMVP		0.64
Mutation Taster		=94/6	polymorphism (auto)

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: rs8192917; hg19: chr14-25102160; COSMIC: COSV53541971;