Genetic Variant GZMM:p.Arg71Trp (chr19-547435-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_005317.4(GZMM):c.211C>T(p.Arg71Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000698 in 1,288,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000070 ( 0 hom. )

Consequence

GZMM
NM_005317.4 missense, splice_region

Scores

Splicing: ADA: 0.00005641

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.72

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.30651134).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GZMM	NM_005317.4 link	c.211C>T	p.Arg71Trp	missense_variant, splice_region_variant	Exon 2 of 5	ENST00000264553.6	NP_005308.2	P51124
GZMM	NM_001258351.2 link	c.94C>T	p.Arg32Trp	missense_variant, splice_region_variant	Exon 2 of 5		NP_001245280.2	P51124

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GZMM	ENST00000264553.6 link	c.211C>T	p.Arg71Trp	missense_variant, splice_region_variant	Exon 2 of 5	1	NM_005317.4	ENSP00000264553.1		P51124
GZMM	ENST00000592501.5 link	c.94C>T	p.Arg32Trp	missense_variant, splice_region_variant	Exon 2 of 5	3		ENSP00000476255.2		U3KQV5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000726

AC:

AN:

137822

Hom.:

AF XY:

0.0000132

AC XY:

AN XY:

76000

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000722

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000698

AC:

AN:

1288786

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

632134

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000477

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000488

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 10, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.211C>T (p.R71W) alteration is located in exon 2 (coding exon 2) of the GZMM gene. This alteration results from a C to T substitution at nucleotide position 211, causing the arginine (R) at amino acid position 71 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Uncertain

0.016

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.50

.;D

Eigen

Benign

-0.82

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.50

T;T

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.31

T;T

MetaSVM

Uncertain

0.12

MutationAssessor

Benign

1.1

.;L

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-2.9

.;D

REVEL

Uncertain

0.35

Sift

Uncertain

0.022

.;D

Sift4G

Uncertain

0.017

D;D

Polyphen

1.0

.;D

Vest4

0.29

MutPred

0.51

.;Loss of sheet (P = 0.1158);

MVP

0.73

MPC

0.19

ClinPred

0.54

GERP RS

-4.0

Varity_R

0.20

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000056

dbscSNV1_RF

Benign

0.058

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