chr14-24632383-G-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004131.6(GZMB):c.280C>G(p.Pro94Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 1,542,766 control chromosomes in the GnomAD database, including 46,906 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.26 ( 5388 hom., cov: 30)

Exomes 𝑓: 0.22 ( 41518 hom. )

Consequence

GZMB
NM_004131.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.43

Variant links:

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]

GZMB links:

ENSG00000258657 (HGNC:58166):

ENSG00000258657 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011751175).

BP6

Variant 14-24632383-G-C is Benign according to our data. Variant chr14-24632383-G-C is described in ClinVar as [Benign]. Clinvar id is 769858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GZMB	NM_004131.6 link	c.280C>G	p.Pro94Ala	missense_variant	Exon 3 of 5	ENST00000216341.9	NP_004122.2	P10144Q67BC3
GZMB	NM_001346011.2 link	c.244C>G	p.Pro82Ala	missense_variant	Exon 3 of 5		NP_001332940.1	J3KQ52Q6XGZ4
GZMB	NR_144343.2 link	n.234-265C>G		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GZMB	ENST00000216341.9 link	c.280C>G	p.Pro94Ala	missense_variant	Exon 3 of 5	1	NM_004131.6	ENSP00000216341.4		P10144

Frequencies

GnomAD3 genomes

AF:

0.260

AC:

39345

AN:

151164

Hom.:

5373

Cov.:

show subpopulations

Gnomad AFR

AF:

0.348

Gnomad AMI

AF:

0.132

Gnomad AMR

AF:

0.199

Gnomad ASJ

AF:

0.248

Gnomad EAS

AF:

0.267

Gnomad SAS

AF:

0.325

Gnomad FIN

AF:

0.189

Gnomad MID

AF:

0.306

Gnomad NFE

AF:

0.229

Gnomad OTH

AF:

0.268

GnomAD3 exomes

AF:

0.210

AC:

47056

AN:

224446

Hom.:

7458

AF XY:

0.214

AC XY:

25855

AN XY:

120664

show subpopulations

Gnomad AFR exome

AF:

0.335

Gnomad AMR exome

AF:

0.130

Gnomad ASJ exome

AF:

0.235

Gnomad EAS exome

AF:

0.247

Gnomad SAS exome

AF:

0.298

Gnomad FIN exome

AF:

0.154

Gnomad NFE exome

AF:

0.196

Gnomad OTH exome

AF:

0.211

GnomAD4 exome

AF:

0.222

AC:

309239

AN:

1391484

Hom.:

41518

Cov.:

AF XY:

0.225

AC XY:

155407

AN XY:

691204

show subpopulations

Gnomad4 AFR exome

AF:

0.353

Gnomad4 AMR exome

AF:

0.139

Gnomad4 ASJ exome

AF:

0.252

Gnomad4 EAS exome

AF:

0.218

Gnomad4 SAS exome

AF:

0.308

Gnomad4 FIN exome

AF:

0.182

Gnomad4 NFE exome

AF:

0.215

Gnomad4 OTH exome

AF:

0.244

GnomAD4 genome

AF:

0.260

AC:

39404

AN:

151282

Hom.:

5388

Cov.:

AF XY:

0.257

AC XY:

18973

AN XY:

73920

show subpopulations

Gnomad4 AFR

AF:

0.348

Gnomad4 AMR

AF:

0.199

Gnomad4 ASJ

AF:

0.248

Gnomad4 EAS

AF:

0.267

Gnomad4 SAS

AF:

0.326

Gnomad4 FIN

AF:

0.189

Gnomad4 NFE

AF:

0.229

Gnomad4 OTH

AF:

0.274

Alfa

AF:

0.250

Hom.:

791

ExAC

AF:

0.245

AC:

29808

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 25, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.45

CADD

Benign

0.0040

DANN

Benign

0.59

DEOGEN2

Benign

0.20

.;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0032

LIST_S2

Benign

0.039

T;T

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.3

.;N

PrimateAI

Benign

0.33

PROVEAN

Benign

3.1

N;N

REVEL

Benign

0.19

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

.;B

Vest4

0.021

MPC

0.18

ClinPred

0.00080

GERP RS

-0.76

Varity_R

0.15

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over