19-544079-C-A

Variant names:

• chr19-544079-C-A
• rs540578685
• NM_005317.4:c.8C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005317.4(GZMM):​c.8C>A​(p.Ala3Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,396,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. A3V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: GZMM NM_005317.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.541
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12484449).

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.8C>A	p.Ala3Asp	missense	Exon 1 of 5	NP_005308.2	P51124
	GZMM	NM_001258351.2		c.-106C>A		5_prime_UTR	Exon 1 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.8C>A	p.Ala3Asp	missense	Exon 1 of 5	ENSP00000264553.1	P51124
	GZMM	ENST00000592501.5	TSL:3	c.-106C>A		5_prime_UTR	Exon 1 of 5	ENSP00000476255.2	U3KQV5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1396494 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 688842

African (AFR) AF: 0.00 AC: 0 AN: 31536

American (AMR) AF: 0.00 AC: 0 AN: 35712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25166

East Asian (EAS) AF: 0.00 AC: 0 AN: 35744

South Asian (SAS) AF: 0.00 AC: 0 AN: 79176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48062

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4350

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078900

Other (OTH) AF: 0.00 AC: 0 AN: 57848

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	0.0078	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	5.0
DANN	Benign	0.90
DEOGEN2	Benign	0.064	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0096	N
LIST_S2	Benign	0.28	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.54
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.73	N
REVEL	Uncertain	0.33
Sift	Benign	0.12	T
Sift4G	Benign	0.082	T
Polyphen		0.79	P
Vest4		0.42
MutPred		0.25		Gain of disorder (P = 0.0667)
MVP		0.61
MPC		0.081
ClinPred		0.11	T
GERP RS		-1.1
PromoterAI		-0.12	Neutral
Varity_R		0.16
gMVP		0.61
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: rs540578685; hg19: chr19-544079;