NM_005317.4:c.382C>T

Variant names:

• chr19-548955-C-T
• rs146201764
• NM_005317.4:c.382C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005317.4(GZMM):​c.382C>T​(p.Arg128Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000535 in 1,593,674 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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. R128Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0029 (3 hom., cov: 28)
  • Exomes 𝑓: 0.00029 (2 hom.)
• Consequence: GZMM NM_005317.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.619
• Publications: 3 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0128625035).
• BP6: Variant 19-548955-C-T is Benign according to our data. Variant chr19-548955-C-T is described in ClinVar as Benign. ClinVar VariationId is 719575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005317.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GZMM	NM_005317.4	MANE Select	c.382C>T	p.Arg128Trp	missense	Exon 4 of 5	NP_005308.2	P51124
	GZMM	NM_001258351.2		c.265C>T	p.Arg89Trp	missense	Exon 4 of 5	NP_001245280.2	U3KQV5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GZMM	ENST00000264553.6	TSL:1 MANE Select	c.382C>T	p.Arg128Trp	missense	Exon 4 of 5	ENSP00000264553.1	P51124
	GZMM	ENST00000592501.5	TSL:3	c.265C>T	p.Arg89Trp	missense	Exon 4 of 5	ENSP00000476255.2	U3KQV5

Frequencies

GnomAD3 genomes AF: 0.00286 AC: 433 AN: 151332 Hom.: 3 Cov.: 28

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000329

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.000761 AC: 175 AN: 229992 AF XY: 0.000595

Gnomad AFR exome AF: 0.0111

Gnomad AMR exome AF: 0.000241

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000501

Gnomad NFE exome AF: 0.0000494

Gnomad OTH exome AF: 0.000179

GnomAD4 exome AF: 0.000290 AC: 418 AN: 1442226 Hom.: 2 Cov.: 34 AF XY: 0.000249 AC XY: 178 AN XY: 714400

African (AFR) AF: 0.0107 AC: 352 AN: 33050

American (AMR) AF: 0.000298 AC: 13 AN: 43694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25384

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39186

South Asian (SAS) AF: 0.0000709 AC: 6 AN: 84608

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51758

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4736

European-Non Finnish (NFE) AF: 0.0000164 AC: 18 AN: 1100552

Other (OTH) AF: 0.000473 AC: 28 AN: 59258

GnomAD4 genome AF: 0.00287 AC: 434 AN: 151448 Hom.: 3 Cov.: 28 AF XY: 0.00269 AC XY: 199 AN XY: 73998

African (AFR) AF: 0.0101 AC: 416 AN: 41230

American (AMR) AF: 0.000329 AC: 5 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4780

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67786

Other (OTH) AF: 0.00237 AC: 5 AN: 2108

Alfa AF: 0.000957 Hom.: 1

Bravo AF: 0.00320

ESP6500AA AF: 0.00755 AC: 33

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.000913 AC: 110

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	0.91	L
PhyloP100		-0.62
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.34
MVP		0.82
MPC		0.33
ClinPred		0.058	T
GERP RS		0.47
Varity_R		0.19
gMVP		0.55
Mutation Taster		=98/2	polymorphism

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: rs146201764; hg19: chr19-548955; COSMIC: COSV104582502;