NM_004131.6:c.321C>T

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
• Publications: 19 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]

GZMH-AS1 (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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004131.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GZMB	NM_004131.6	MANE Select	c.321C>T	p.Asn107Asn	synonymous	Exon 3 of 5	NP_004122.2	P10144
	GZMB	NM_001346011.2		c.285C>T	p.Asn95Asn	synonymous	Exon 3 of 5	NP_001332940.1	J3KQ52
	GZMB	NR_144343.2		n.234-224C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GZMB	ENST00000216341.9	TSL:1 MANE Select	c.321C>T	p.Asn107Asn	synonymous	Exon 3 of 5	ENSP00000216341.4	P10144
	GZMB	ENST00000415355.7	TSL:2	c.285C>T	p.Asn95Asn	synonymous	Exon 3 of 5	ENSP00000387385.3	J3KQ52
	GZMB	ENST00000859020.1		c.261C>T	p.Asn87Asn	synonymous	Exon 3 of 5	ENSP00000529079.1

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.352 AC: 10833 AN: 30812

American (AMR) AF: 0.133 AC: 5621 AN: 42230

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 6123 AN: 24622

East Asian (EAS) AF: 0.214 AC: 8167 AN: 38114

South Asian (SAS) AF: 0.304 AC: 24464 AN: 80396

European-Finnish (FIN) AF: 0.174 AC: 8646 AN: 49590

Middle Eastern (MID) AF: 0.284 AC: 1206 AN: 4250

European-Non Finnish (NFE) AF: 0.209 AC: 218348 AN: 1043194

Other (OTH) AF: 0.238 AC: 13548 AN: 56884

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.344 AC: 13914 AN: 40398

American (AMR) AF: 0.195 AC: 2949 AN: 15108

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 845 AN: 3430

East Asian (EAS) AF: 0.262 AC: 1327 AN: 5068

South Asian (SAS) AF: 0.321 AC: 1494 AN: 4654

European-Finnish (FIN) AF: 0.185 AC: 1926 AN: 10426

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.227 AC: 15257 AN: 67330

Other (OTH) AF: 0.271 AC: 560 AN: 2068

Alfa AF: 0.253 Hom.: 960

Asia WGS AF: 0.335 AC: 1165 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.59
DANN	Benign	0.68
PhyloP100		-2.2
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: rs1126639; hg19: chr14-25101548; COSMIC: COSV53540565;