rs2273844

Variant names:

• chr14-24634208-G-A
• rs2273844
• ENST00000415355.7:c.-97C>T

Variant summary

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

The ENST00000415355.7(GZMB):​c.-97C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 1,562,184 control chromosomes in the GnomAD database, including 44,879 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 0.26 (5216 hom., cov: 32)
  • Exomes 𝑓: 0.23 (39663 hom.)
• Consequence: GZMB ENST00000415355.7 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.129
• Publications: 40 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=-0.75).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.332 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GZMH-AS1	XR_007064087.1	n.248-88G>A		intron_variant	Intron 1 of 2
GZMB	NM_004131.6	c.-48C>T		upstream_gene_variant		ENST00000216341.9	NP_004122.2
GZMB	NM_001346011.2	c.-97C>T		upstream_gene_variant			NP_001332940.1
GZMB	NR_144343.2	n.-18C>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GZMB	ENST00000216341.9	c.-48C>T		upstream_gene_variant		1	NM_004131.6	ENSP00000216341.4

Frequencies

GnomAD3 genomes AF: 0.256 AC: 38893 AN: 151942 Hom.: 5200 Cov.: 32

Gnomad AFR AF: 0.336

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.228

Gnomad EAS AF: 0.266

Gnomad SAS AF: 0.328

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.227

Gnomad OTH AF: 0.271

GnomAD2 exomes AF: 0.242 AC: 42195 AN: 174628 AF XY: 0.247

Gnomad AFR exome AF: 0.354

Gnomad AMR exome AF: 0.152

Gnomad ASJ exome AF: 0.250

Gnomad EAS exome AF: 0.273

Gnomad FIN exome AF: 0.193

Gnomad NFE exome AF: 0.236

Gnomad OTH exome AF: 0.238

GnomAD4 exome AF: 0.233 AC: 329047 AN: 1410124 Hom.: 39663 Cov.: 32 AF XY: 0.236 AC XY: 164042 AN XY: 696222

African (AFR) AF: 0.350 AC: 11498 AN: 32834

American (AMR) AF: 0.160 AC: 5737 AN: 35950

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 6201 AN: 25184

East Asian (EAS) AF: 0.226 AC: 8578 AN: 37924

South Asian (SAS) AF: 0.315 AC: 25216 AN: 80142

European-Finnish (FIN) AF: 0.200 AC: 10030 AN: 50144

Middle Eastern (MID) AF: 0.300 AC: 1708 AN: 5700

European-Non Finnish (NFE) AF: 0.226 AC: 245326 AN: 1083676

Other (OTH) AF: 0.252 AC: 14753 AN: 58570

GnomAD4 genome AF: 0.256 AC: 38955 AN: 152060 Hom.: 5216 Cov.: 32 AF XY: 0.253 AC XY: 18775 AN XY: 74348

African (AFR) AF: 0.337 AC: 13965 AN: 41462

American (AMR) AF: 0.196 AC: 2987 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.228 AC: 792 AN: 3468

East Asian (EAS) AF: 0.266 AC: 1371 AN: 5162

South Asian (SAS) AF: 0.329 AC: 1583 AN: 4816

European-Finnish (FIN) AF: 0.191 AC: 2022 AN: 10586

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.227 AC: 15442 AN: 67970

Other (OTH) AF: 0.277 AC: 584 AN: 2112

Alfa AF: 0.246 Hom.: 8824

Bravo AF: 0.260

Asia WGS AF: 0.337 AC: 1174 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	13
DANN	Uncertain	1.0
PhyloP100		-0.13
PromoterAI		-0.057	Neutral
Mutation Taster		=154/46	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: rs2273844; hg19: chr14-25103414; COSMIC: COSV53540526; COSMIC: COSV53540526;