19-548577-C-G

Variant names:

• chr19-548577-C-G
• rs1980374992
• NM_005317.4:c.248C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005317.4(GZMM):​c.248C>G​(p.Thr83Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign 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. T83N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GZMM NM_005317.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.37
• 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_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.041917384).

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.248C>G	p.Thr83Ser	missense	Exon 3 of 5	NP_005308.2	P51124
	GZMM	NM_001258351.2		c.131C>G	p.Thr44Ser	missense	Exon 3 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.248C>G	p.Thr83Ser	missense	Exon 3 of 5	ENSP00000264553.1	P51124
	GZMM	ENST00000592501.5	TSL:3	c.131C>G	p.Thr44Ser	missense	Exon 3 of 5	ENSP00000476255.2	U3KQV5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	0.012
DANN	Benign	0.57
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.091	T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.61	N
PhyloP100		-3.4
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.89	N
REVEL	Benign	0.22
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.49		Gain of disorder (P = 0.0686)
MVP		0.43
MPC		0.051
ClinPred		0.033	T
GERP RS		-5.3
Varity_R		0.080
gMVP		0.23
Mutation Taster		=95/5	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: rs1980374992; hg19: chr19-548577;