rs8192917

Positions:

• chr14-24632954-C-T

Variant summary

Our verdict is Benign. Variant got -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. 12/20 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 same amino acid change has been previously reported as Likely benignin 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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
GZMB	NM_004131.6	c.164G>A	p.Arg55Gln	missense_variant	2/5	ENST00000216341.9	NP_004122.2
GZMB	NM_001346011.2	c.128G>A	p.Arg43Gln	missense_variant	2/5		NP_001332940.1
GZMB	NR_144343.2	n.194G>A		non_coding_transcript_exon_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GZMB	ENST00000216341.9	c.164G>A	p.Arg55Gln	missense_variant	2/5	1	NM_004131.6	ENSP00000216341	P2
	ENST00000555300.1	n.177+9828C>T		intron_variant, non_coding_transcript_variant		5

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

GnomAD3 exomes AF: 0.755 AC: 189367 AN: 250770 Hom.: 72116 AF XY: 0.751 AC XY: 101780 AN XY: 135500

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 SAS exome AF: 0.683

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

Gnomad4 AMR exome AF: 0.840

Gnomad4 ASJ exome AF: 0.755

Gnomad4 EAS exome AF: 0.773

Gnomad4 SAS exome AF: 0.684

Gnomad4 FIN exome AF: 0.800

Gnomad4 NFE exome AF: 0.773

Gnomad4 OTH exome AF: 0.745

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

Gnomad4 AMR AF: 0.794

Gnomad4 ASJ AF: 0.771

Gnomad4 EAS AF: 0.731

Gnomad4 SAS AF: 0.671

Gnomad4 FIN AF: 0.808

Gnomad4 NFE AF: 0.772

Gnomad4 OTH AF: 0.709

Alfa AF: 0.755 Hom.: 112521

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;.;.;.
MutationTaster	Benign	1.0	P;P;P;P;P
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

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;