chr14-24632500-G-T

Variant names:

• chr14-24632500-G-T
• rs10873219
• NM_004131.6:c.204-41C>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.204-41C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 1,612,180 control chromosomes in the GnomAD database, including 31,633 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (2873 hom., cov: 31)
  • Exomes 𝑓: 0.20 (28760 hom.)
• Consequence: GZMB NM_004131.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.974
• Publications: 20 publications found

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):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.235 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GZMB	NM_004131.6	c.204-41C>A		intron_variant	Intron 2 of 4	ENST00000216341.9	NP_004122.2
GZMB	NM_001346011.2	c.168-41C>A		intron_variant	Intron 2 of 4		NP_001332940.1
GZMB	NR_144343.2	n.234-382C>A		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GZMB	ENST00000216341.9	c.204-41C>A		intron_variant	Intron 2 of 4	1	NM_004131.6	ENSP00000216341.4

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29656 AN: 151768 Hom.: 2863 Cov.: 31

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.128

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.195

Gnomad EAS AF: 0.179

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.213

Gnomad NFE AF: 0.198

Gnomad OTH AF: 0.202

GnomAD2 exomes AF: 0.194 AC: 48529 AN: 250480 AF XY: 0.199

Gnomad AFR exome AF: 0.213

Gnomad AMR exome AF: 0.129

Gnomad ASJ exome AF: 0.209

Gnomad EAS exome AF: 0.175

Gnomad FIN exome AF: 0.180

Gnomad NFE exome AF: 0.203

Gnomad OTH exome AF: 0.188

GnomAD4 exome AF: 0.196 AC: 286762 AN: 1460292 Hom.: 28760 Cov.: 33 AF XY: 0.198 AC XY: 144004 AN XY: 726486

African (AFR) AF: 0.213 AC: 7122 AN: 33430

American (AMR) AF: 0.133 AC: 5958 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 5392 AN: 26068

East Asian (EAS) AF: 0.147 AC: 5822 AN: 39682

South Asian (SAS) AF: 0.239 AC: 20624 AN: 86146

European-Finnish (FIN) AF: 0.183 AC: 9756 AN: 53384

Middle Eastern (MID) AF: 0.241 AC: 1391 AN: 5762

European-Non Finnish (NFE) AF: 0.197 AC: 218459 AN: 1110842

Other (OTH) AF: 0.203 AC: 12238 AN: 60318

GnomAD4 genome AF: 0.195 AC: 29673 AN: 151888 Hom.: 2873 Cov.: 31 AF XY: 0.192 AC XY: 14268 AN XY: 74232

African (AFR) AF: 0.207 AC: 8559 AN: 41398

American (AMR) AF: 0.158 AC: 2411 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 677 AN: 3470

East Asian (EAS) AF: 0.179 AC: 919 AN: 5144

South Asian (SAS) AF: 0.246 AC: 1178 AN: 4784

European-Finnish (FIN) AF: 0.175 AC: 1851 AN: 10562

Middle Eastern (MID) AF: 0.212 AC: 62 AN: 292

European-Non Finnish (NFE) AF: 0.198 AC: 13462 AN: 67946

Other (OTH) AF: 0.207 AC: 438 AN: 2112

Alfa AF: 0.201 Hom.: 6415

Bravo AF: 0.194

Asia WGS AF: 0.225 AC: 784 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.6
DANN	Benign	0.42
PhyloP100		0.97
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs10873219; hg19: chr14-25101706; COSMIC: COSV53542960;