NM_004131.6:c.739T>C

Variant names:

• chr14-24631076-A-G
• rs2236338
• NM_004131.6:c.739T>C

Variant summary

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

The NM_004131.6(GZMB):​c.739T>C​(p.Tyr247His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 1,609,608 control chromosomes in the GnomAD database, including 46,605 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. Y247C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.25 (5074 hom., cov: 32)
  • Exomes 𝑓: 0.23 (41531 hom.)
• Consequence: GZMB NM_004131.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.798
• Publications: 58 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0058291852).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.321 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GZMB	NM_004131.6	MANE Select	c.739T>C	p.Tyr247His	missense	Exon 5 of 5	NP_004122.2
	GZMB	NM_001346011.2		c.703T>C	p.Tyr235His	missense	Exon 5 of 5	NP_001332940.1
	GZMB	NR_144343.2		n.633T>C		non_coding_transcript_exon	Exon 4 of 4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GZMB	ENST00000216341.9	TSL:1 MANE Select	c.739T>C	p.Tyr247His	missense	Exon 5 of 5	ENSP00000216341.4
	GZMB	ENST00000415355.7	TSL:2	c.703T>C	p.Tyr235His	missense	Exon 5 of 5	ENSP00000387385.3
	GZMB	ENST00000859020.1		c.679T>C	p.Tyr227His	missense	Exon 5 of 5	ENSP00000529079.1

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38572 AN: 151936 Hom.: 5052 Cov.: 32

Gnomad AFR AF: 0.325

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.195

Gnomad ASJ AF: 0.246

Gnomad EAS AF: 0.282

Gnomad SAS AF: 0.334

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.229

Gnomad OTH AF: 0.266

GnomAD2 exomes AF: 0.239 AC: 60130 AN: 251230 AF XY: 0.246

Gnomad AFR exome AF: 0.330

Gnomad AMR exome AF: 0.147

Gnomad ASJ exome AF: 0.259

Gnomad EAS exome AF: 0.281

Gnomad FIN exome AF: 0.187

Gnomad NFE exome AF: 0.234

Gnomad OTH exome AF: 0.233

GnomAD4 exome AF: 0.235 AC: 341981 AN: 1457554 Hom.: 41531 Cov.: 30 AF XY: 0.238 AC XY: 172469 AN XY: 725336

African (AFR) AF: 0.332 AC: 11067 AN: 33346

American (AMR) AF: 0.154 AC: 6884 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.260 AC: 6780 AN: 26086

East Asian (EAS) AF: 0.236 AC: 9375 AN: 39666

South Asian (SAS) AF: 0.320 AC: 27580 AN: 86140

European-Finnish (FIN) AF: 0.192 AC: 10270 AN: 53408

Middle Eastern (MID) AF: 0.312 AC: 1797 AN: 5760

European-Non Finnish (NFE) AF: 0.228 AC: 253123 AN: 1108230

Other (OTH) AF: 0.251 AC: 15105 AN: 60216

GnomAD4 genome AF: 0.254 AC: 38645 AN: 152054 Hom.: 5074 Cov.: 32 AF XY: 0.251 AC XY: 18684 AN XY: 74314

African (AFR) AF: 0.325 AC: 13480 AN: 41434

American (AMR) AF: 0.194 AC: 2973 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 853 AN: 3472

East Asian (EAS) AF: 0.282 AC: 1456 AN: 5166

South Asian (SAS) AF: 0.335 AC: 1617 AN: 4826

European-Finnish (FIN) AF: 0.183 AC: 1933 AN: 10588

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

European-Non Finnish (NFE) AF: 0.229 AC: 15545 AN: 67962

Other (OTH) AF: 0.272 AC: 576 AN: 2114

Alfa AF: 0.244 Hom.: 14686

Bravo AF: 0.257

TwinsUK AF: 0.234 AC: 867

ALSPAC AF: 0.235 AC: 907

ESP6500AA AF: 0.318 AC: 1401

ESP6500EA AF: 0.238 AC: 2050

ExAC AF: 0.246 AC: 29845

Asia WGS AF: 0.337 AC: 1173 AN: 3478

EpiCase AF: 0.241

EpiControl AF: 0.251

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	4.1
DANN	Benign	0.29
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0057	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.61	N
PhyloP100		-0.80
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.14
Sift	Benign	0.34	T
Sift4G	Benign	0.25	T
Polyphen		0.0	B
Vest4		0.034
MPC		0.24
ClinPred		0.0023	T
GERP RS		-1.6
Varity_R		0.12
gMVP		0.41
Mutation Taster		=97/3	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: rs2236338; hg19: chr14-25100282; COSMIC: COSV53540498; COSMIC: COSV53540498;