chr14-24632342-G-A

Variant names:

• chr14-24632342-G-A
• rs1126639
• NM_004131.6:c.321C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004131.6(GZMB):​c.321C>T​(p.Asn107Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 1,519,772 control chromosomes in the GnomAD database, including 45,760 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5238 hom., cov: 29)
  • Exomes 𝑓: 0.22 (40522 hom.)
• Consequence: GZMB NM_004131.6 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.15

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 14-24632342-G-A is Benign according to our data. Variant chr14-24632342-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 769857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.15 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.34 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GZMB	NM_004131.6	c.321C>T	p.Asn107Asn	synonymous_variant	Exon 3 of 5	ENST00000216341.9	NP_004122.2
GZMB	NM_001346011.2	c.285C>T	p.Asn95Asn	synonymous_variant	Exon 3 of 5		NP_001332940.1
GZMB	NR_144343.2	n.234-224C>T		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GZMB	ENST00000216341.9	c.321C>T	p.Asn107Asn	synonymous_variant	Exon 3 of 5	1	NM_004131.6	ENSP00000216341.4

Frequencies

GnomAD3 genomes AF: 0.257 AC: 38416 AN: 149558 Hom.: 5222 Cov.: 29

Gnomad AFR AF: 0.344

Gnomad AMI AF: 0.128

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.246

Gnomad EAS AF: 0.262

Gnomad SAS AF: 0.320

Gnomad FIN AF: 0.185

Gnomad MID AF: 0.312

Gnomad NFE AF: 0.227

Gnomad OTH AF: 0.265

GnomAD2 exomes AF: 0.194 AC: 42014 AN: 216556 AF XY: 0.199

Gnomad AFR exome AF: 0.311

Gnomad AMR exome AF: 0.121

Gnomad ASJ exome AF: 0.233

Gnomad EAS exome AF: 0.231

Gnomad FIN exome AF: 0.133

Gnomad NFE exome AF: 0.176

Gnomad OTH exome AF: 0.200

GnomAD4 exome AF: 0.217 AC: 296956 AN: 1370092 Hom.: 40522 Cov.: 33 AF XY: 0.220 AC XY: 149633 AN XY: 681390

Gnomad4 AFR exome AF: 0.352 AC: 10833 AN: 30812

Gnomad4 AMR exome AF: 0.133 AC: 5621 AN: 42230

Gnomad4 ASJ exome AF: 0.249 AC: 6123 AN: 24622

Gnomad4 EAS exome AF: 0.214 AC: 8167 AN: 38114

Gnomad4 SAS exome AF: 0.304 AC: 24464 AN: 80396

Gnomad4 FIN exome AF: 0.174 AC: 8646 AN: 49590

Gnomad4 NFE exome AF: 0.209 AC: 218348 AN: 1043194

Gnomad4 Remaining exome AF: 0.238 AC: 13548 AN: 56884

GnomAD4 genome AF: 0.257 AC: 38478 AN: 149680 Hom.: 5238 Cov.: 29 AF XY: 0.253 AC XY: 18490 AN XY: 73076

Gnomad4 AFR AF: 0.344 AC: 0.344423 AN: 0.344423

Gnomad4 AMR AF: 0.195 AC: 0.195195 AN: 0.195195

Gnomad4 ASJ AF: 0.246 AC: 0.246356 AN: 0.246356

Gnomad4 EAS AF: 0.262 AC: 0.261839 AN: 0.261839

Gnomad4 SAS AF: 0.321 AC: 0.321014 AN: 0.321014

Gnomad4 FIN AF: 0.185 AC: 0.18473 AN: 0.18473

Gnomad4 NFE AF: 0.227 AC: 0.2266 AN: 0.2266

Gnomad4 OTH AF: 0.271 AC: 0.270793 AN: 0.270793

Alfa AF: 0.253 Hom.: 960

Asia WGS AF: 0.335 AC: 1165 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 25, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.59
DANN	Benign	0.68
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

Publications

LitVar

Other links and lift over

dbSNP: rs1126639; hg19: chr14-25101548; COSMIC: COSV53540565;