dbSNP rs763963542: GZMB:p.Arg221Leu (chr14-24631153-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004131.6(GZMB):c.662G>T(p.Arg221Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. R221Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GZMB
NM_004131.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -11.6

Publications

1 publications found

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:

GZMH-AS1 (HGNC:58166):

GZMH-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.095244616).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GZMB	NM_004131.6	MANE Select	c.662G>T	p.Arg221Leu	missense	Exon 5 of 5	NP_004122.2	P10144
GZMB	NM_001346011.2		c.626G>T	p.Arg209Leu	missense	Exon 5 of 5	NP_001332940.1	J3KQ52
GZMB	NR_144343.2		n.556G>T		non_coding_transcript_exon	Exon 4 of 4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GZMB	ENST00000216341.9	TSL:1 MANE Select	c.662G>T	p.Arg221Leu	missense	Exon 5 of 5	ENSP00000216341.4	P10144
GZMB	ENST00000415355.7	TSL:2	c.626G>T	p.Arg209Leu	missense	Exon 5 of 5	ENSP00000387385.3	J3KQ52
GZMB	ENST00000859020.1		c.602G>T	p.Arg201Leu	missense	Exon 5 of 5	ENSP00000529079.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251386

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460684

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726736

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33454

American (AMR)

AF:

0.0000224

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110938

Other (OTH)

AF:

0.00

AC:

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.46

CADD

Benign

0.0010

(source)

DANN

Benign

0.42

DEOGEN2

Uncertain

0.56

Eigen

Benign

-2.9

Eigen_PC

Benign

-3.0

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.050

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.095

MetaSVM

Benign

-0.76

MutationAssessor

Benign

-0.22

PhyloP100

-12

PrimateAI

Benign

0.20

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.34

Sift

Benign

0.54

Sift4G

Benign

0.81

Polyphen

0.0010

Vest4

0.13

MutPred

0.48

Loss of methylation at R221 (P = 0.0209)

MVP

0.49

MPC

0.23

ClinPred

0.048

GERP RS

-10

Varity_R

0.28

gMVP

0.43

Mutation Taster

=91/9

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over