Genetic Variant GZMM:p.Arg101Ser (chr19-548630-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The NM_005317.4(GZMM):c.301C>A(p.Arg101Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00443 in 1,613,624 control chromosomes in the GnomAD database, including 248 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R101C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.023 ( 138 hom., cov: 31)

Exomes 𝑓: 0.0025 ( 110 hom. )

Consequence

GZMM
NM_005317.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.46

Variant links:

Genes affected

GZMM (HGNC:4712): (granzyme M) Human natural killer (NK) cells and activated lymphocytes express and store a distinct subset of neutral serine proteases together with proteoglycans and other immune effector molecules in large cytoplasmic granules. These serine proteases are collectively termed granzymes and include 4 distinct gene products: granzyme A, granzyme B, granzyme H, and the protein encoded by this gene, granzyme M. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

GZMM 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=0.005142659).

BP6

Variant 19-548630-C-A is Benign according to our data. Variant chr19-548630-C-A is described in ClinVar as [Benign]. Clinvar id is 768945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0775 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GZMM	NM_005317.4 link	c.301C>A	p.Arg101Ser	missense_variant	Exon 3 of 5	ENST00000264553.6	NP_005308.2	P51124
GZMM	NM_001258351.2 link	c.184C>A	p.Arg62Ser	missense_variant	Exon 3 of 5		NP_001245280.2	P51124

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GZMM	ENST00000264553.6 link	c.301C>A	p.Arg101Ser	missense_variant	Exon 3 of 5	1	NM_005317.4	ENSP00000264553.1		P51124
GZMM	ENST00000592501.5 link	c.184C>A	p.Arg62Ser	missense_variant	Exon 3 of 5	3		ENSP00000476255.2		U3KQV5

Frequencies

GnomAD3 genomes

AF:

0.0229

AC:

3482

AN:

152072

Hom.:

138

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0797

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00655

Gnomad ASJ

AF:

0.00980

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000280

Gnomad OTH

AF:

0.0153

GnomAD3 exomes

AF:

0.00646

AC:

1619

AN:

250644

Hom.:

AF XY:

0.00473

AC XY:

642

AN XY:

135600

show subpopulations

Gnomad AFR exome

AF:

0.0844

Gnomad AMR exome

AF:

0.00292

Gnomad ASJ exome

AF:

0.00817

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000380

Gnomad OTH exome

AF:

0.00359

GnomAD4 exome

AF:

0.00250

AC:

3652

AN:

1461436

Hom.:

110

Cov.:

AF XY:

0.00217

AC XY:

1580

AN XY:

727038

show subpopulations

Gnomad4 AFR exome

AF:

0.0841

Gnomad4 AMR exome

AF:

0.00335

Gnomad4 ASJ exome

AF:

0.00858

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000128

Gnomad4 OTH exome

AF:

0.00502

GnomAD4 genome

AF:

0.0230

AC:

3495

AN:

152188

Hom.:

138

Cov.:

AF XY:

0.0218

AC XY:

1620

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.0797

Gnomad4 AMR

AF:

0.00654

Gnomad4 ASJ

AF:

0.00980

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000280

Gnomad4 OTH

AF:

0.0151

Alfa

AF:

0.00428

Hom.:

Bravo

AF:

0.0258

ESP6500AA

AF:

0.0883

AC:

389

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.00790

AC:

959

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000296

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

- -

Dec 31, 2019

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

0.15

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.35

CADD

Benign

0.79

DANN

Benign

0.73

DEOGEN2

Benign

0.11

.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.34

T;T

MetaRNN

Benign

0.0051

T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

0.40

.;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.19

.;N

REVEL

Benign

0.18

Sift

Benign

0.79

.;T

Sift4G

Benign

0.69

T;T

Polyphen

0.36

.;B

Vest4

0.18

MVP

0.55

MPC

0.064

ClinPred

0.0043

GERP RS

-3.0

Varity_R

0.18

gMVP

0.33

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

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