19-547337-C-G

Variant names:

• chr19-547337-C-G
• rs769729181
• NM_005317.4:c.113C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005317.4(GZMM):​c.113C>G​(p.Pro38Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,425,536 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. P38L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GZMM NM_005317.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.872
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977

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.113C>G	p.Pro38Arg	missense	Exon 2 of 5	NP_005308.2	P51124
	GZMM	NM_001258351.2		c.-5C>G		5_prime_UTR	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.113C>G	p.Pro38Arg	missense	Exon 2 of 5	ENSP00000264553.1	P51124
	GZMM	ENST00000592501.5	TSL:3	c.-5C>G		5_prime_UTR	Exon 2 of 5	ENSP00000476255.2	U3KQV5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1425536 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 708700

African (AFR) AF: 0.0000320 AC: 1 AN: 31290

American (AMR) AF: 0.00 AC: 0 AN: 40186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25278

East Asian (EAS) AF: 0.00 AC: 0 AN: 35924

South Asian (SAS) AF: 0.00 AC: 0 AN: 81766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51030

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5666

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1095524

Other (OTH) AF: 0.0000170 AC: 1 AN: 58872

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.081	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.87
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-8.0	D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.86		Gain of MoRF binding (P = 0.0029)
MVP		0.89
MPC		0.37
ClinPred		0.94	D
GERP RS		1.5
Varity_R		0.53
gMVP		0.84
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs769729181; hg19: chr19-547337;