19-547435-C-T

Variant names:

• chr19-547435-C-T
• rs1408535175
• NM_005317.4:c.211C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

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. 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
• Publications: 1 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30651134).

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.211C>T	p.Arg71Trp	missense splice_region	Exon 2 of 5	NP_005308.2	P51124
	GZMM	NM_001258351.2		c.94C>T	p.Arg32Trp	missense splice_region	Exon 2 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.211C>T	p.Arg71Trp	missense splice_region	Exon 2 of 5	ENSP00000264553.1	P51124
	GZMM	ENST00000592501.5	TSL:3	c.94C>T	p.Arg32Trp	missense splice_region	Exon 2 of 5	ENSP00000476255.2	U3KQV5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000726 AC: 1 AN: 137822 AF XY: 0.0000132

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000698 AC: 9 AN: 1288786 Hom.: 0 Cov.: 33 AF XY: 0.0000111 AC XY: 7 AN XY: 632134

African (AFR) AF: 0.00 AC: 0 AN: 27134

American (AMR) AF: 0.00 AC: 0 AN: 25588

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19798

East Asian (EAS) AF: 0.00 AC: 0 AN: 31896

South Asian (SAS) AF: 0.0000477 AC: 3 AN: 62926

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38096

Middle Eastern (MID) AF: 0.000197 AC: 1 AN: 5084

European-Non Finnish (NFE) AF: 0.00000488 AC: 5 AN: 1025584

Other (OTH) AF: 0.00 AC: 0 AN: 52680

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D
Eigen	Benign	-0.82
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.50	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Benign	1.1	L
PhyloP100		-2.7
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.017	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	D
GERP RS		-4.0
Varity_R		0.20
gMVP		0.49
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs1408535175; hg19: chr19-547435; COSMIC: COSV52742350;