rs77680573

Variant names:

• chr19-548630-C-A
• rs77680573
• NM_005317.4:c.301C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-548630-C-A
• chr19-548630-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005317.4(GZMM):​c.301C>A​(p.Arg101Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00443 in 1,613,624 control chromosomes in the GnomAD database, including 248 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. R101C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.023 (138 hom., cov: 31)
  • Exomes 𝑓: 0.0025 (110 hom.)
• Consequence: GZMM NM_005317.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.46
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005142659).
• BP6: Variant 19-548630-C-A is Benign according to our data. Variant chr19-548630-C-A is described in ClinVar as Benign. ClinVar VariationId is 768945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0775 is higher than 0.05.

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.301C>A	p.Arg101Ser	missense	Exon 3 of 5	NP_005308.2	P51124
	GZMM	NM_001258351.2		c.184C>A	p.Arg62Ser	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.301C>A	p.Arg101Ser	missense	Exon 3 of 5	ENSP00000264553.1	P51124
	GZMM	ENST00000592501.5	TSL:3	c.184C>A	p.Arg62Ser	missense	Exon 3 of 5	ENSP00000476255.2	U3KQV5

Frequencies

GnomAD3 genomes AF: 0.0229 AC: 3482 AN: 152072 Hom.: 138 Cov.: 31

Gnomad AFR AF: 0.0797

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00655

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000280

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.00646 AC: 1619 AN: 250644 AF XY: 0.00473

Gnomad AFR exome AF: 0.0844

Gnomad AMR exome AF: 0.00292

Gnomad ASJ exome AF: 0.00817

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000380

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00250 AC: 3652 AN: 1461436 Hom.: 110 Cov.: 33 AF XY: 0.00217 AC XY: 1580 AN XY: 727038

African (AFR) AF: 0.0841 AC: 2816 AN: 33466

American (AMR) AF: 0.00335 AC: 150 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00858 AC: 224 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53242

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5766

European-Non Finnish (NFE) AF: 0.000128 AC: 142 AN: 1111822

Other (OTH) AF: 0.00502 AC: 303 AN: 60368

GnomAD4 genome AF: 0.0230 AC: 3495 AN: 152188 Hom.: 138 Cov.: 31 AF XY: 0.0218 AC XY: 1620 AN XY: 74418

African (AFR) AF: 0.0797 AC: 3310 AN: 41506

American (AMR) AF: 0.00654 AC: 100 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00980 AC: 34 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000280 AC: 19 AN: 67970

Other (OTH) AF: 0.0151 AC: 32 AN: 2114

Alfa AF: 0.00858 Hom.: 81

Bravo AF: 0.0258

ESP6500AA AF: 0.0883 AC: 389

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00790 AC: 959

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000296

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	0.15
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	0.79
DANN	Benign	0.73
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.40	N
PhyloP100		-1.5
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.18
Sift	Benign	0.79	T
Sift4G	Benign	0.69	T
Polyphen		0.36	B
Vest4		0.18
MVP		0.55
MPC		0.064
ClinPred		0.0043	T
GERP RS		-3.0
Varity_R		0.18
gMVP		0.33
Mutation Taster		=97/3	polymorphism (auto)

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: rs77680573; hg19: chr19-548630;