NM_004131.6:c.280C>G

Variant names:

• chr14-24632383-G-C
• rs11539752
• NM_004131.6:c.280C>G

Variant summary

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

The NM_004131.6(GZMB):​c.280C>G​(p.Pro94Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 1,542,766 control chromosomes in the GnomAD database, including 46,906 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5388 hom., cov: 30)
  • Exomes 𝑓: 0.22 (41518 hom.)
• Consequence: GZMB NM_004131.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.43
• Publications: 39 publications found

Genes affected

GZMB (HGNC:4709): (granzyme B) This gene encodes a member of the granzyme subfamily of proteins, part of the peptidase S1 family of serine proteases. The encoded preproprotein is secreted by natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) and proteolytically processed to generate the active protease, which induces target cell apoptosis. This protein also processes cytokines and degrades extracellular matrix proteins, and these roles are implicated in chronic inflammation and wound healing. Expression of this gene may be elevated in human patients with cardiac fibrosis. [provided by RefSeq, Sep 2016]

ENSG00000258657 (HGNC:58166):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011751175).
• BP6: Variant 14-24632383-G-C is Benign according to our data. Variant chr14-24632383-G-C is described in ClinVar as Benign. ClinVar VariationId is 769858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004131.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GZMB	NM_004131.6	MANE Select	c.280C>G	p.Pro94Ala	missense	Exon 3 of 5	NP_004122.2
	GZMB	NM_001346011.2		c.244C>G	p.Pro82Ala	missense	Exon 3 of 5	NP_001332940.1
	GZMB	NR_144343.2		n.234-265C>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GZMB	ENST00000216341.9	TSL:1 MANE Select	c.280C>G	p.Pro94Ala	missense	Exon 3 of 5	ENSP00000216341.4
	GZMB	ENST00000415355.7	TSL:2	c.244C>G	p.Pro82Ala	missense	Exon 3 of 5	ENSP00000387385.3
	GZMB	ENST00000530830.1	TSL:5	n.*203C>G		non_coding_transcript_exon	Exon 4 of 6	ENSP00000435084.1

Frequencies

GnomAD3 genomes AF: 0.260 AC: 39345 AN: 151164 Hom.: 5373 Cov.: 30

Gnomad AFR AF: 0.348

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.199

Gnomad ASJ AF: 0.248

Gnomad EAS AF: 0.267

Gnomad SAS AF: 0.325

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.306

Gnomad NFE AF: 0.229

Gnomad OTH AF: 0.268

GnomAD2 exomes AF: 0.210 AC: 47056 AN: 224446 AF XY: 0.214

Gnomad AFR exome AF: 0.335

Gnomad AMR exome AF: 0.130

Gnomad ASJ exome AF: 0.235

Gnomad EAS exome AF: 0.247

Gnomad FIN exome AF: 0.154

Gnomad NFE exome AF: 0.196

Gnomad OTH exome AF: 0.211

GnomAD4 exome AF: 0.222 AC: 309239 AN: 1391484 Hom.: 41518 Cov.: 33 AF XY: 0.225 AC XY: 155407 AN XY: 691204

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.353 AC: 11114 AN: 31452

American (AMR) AF: 0.139 AC: 5927 AN: 42616

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 6237 AN: 24744

East Asian (EAS) AF: 0.218 AC: 8388 AN: 38484

South Asian (SAS) AF: 0.308 AC: 25144 AN: 81582

European-Finnish (FIN) AF: 0.182 AC: 9201 AN: 50636

Middle Eastern (MID) AF: 0.292 AC: 1477 AN: 5058

European-Non Finnish (NFE) AF: 0.215 AC: 227641 AN: 1059018

Other (OTH) AF: 0.244 AC: 14110 AN: 57894

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.260 AC: 39404 AN: 151282 Hom.: 5388 Cov.: 30 AF XY: 0.257 AC XY: 18973 AN XY: 73920

African (AFR) AF: 0.348 AC: 14312 AN: 41106

American (AMR) AF: 0.199 AC: 3028 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 860 AN: 3462

East Asian (EAS) AF: 0.267 AC: 1373 AN: 5148

South Asian (SAS) AF: 0.326 AC: 1538 AN: 4718

European-Finnish (FIN) AF: 0.189 AC: 1987 AN: 10530

Middle Eastern (MID) AF: 0.298 AC: 87 AN: 292

European-Non Finnish (NFE) AF: 0.229 AC: 15527 AN: 67806

Other (OTH) AF: 0.274 AC: 572 AN: 2088

Alfa AF: 0.250 Hom.: 791

ExAC AF: 0.245 AC: 29808

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 25, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	0.0040
DANN	Benign	0.59
DEOGEN2	Benign	0.20	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0032	N
LIST_S2	Benign	0.039	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.3	N
PhyloP100		-1.4
PrimateAI	Benign	0.33	T
PROVEAN	Benign	3.1	N
REVEL	Benign	0.19
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.021
MPC		0.18
ClinPred		0.00080	T
GERP RS		-0.76
Varity_R		0.15
gMVP		0.52
Mutation Taster		=92/8	polymorphism (auto)

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: rs11539752; hg19: chr14-25101589; COSMIC: COSV53539969;