14-24632383-G-C

Position:

• chr14-24632383-G-C

Variant summary

Our verdict is Benign. Variant got -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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GZMB	NM_004131.6	c.280C>G	p.Pro94Ala	missense_variant	3/5	ENST00000216341.9	NP_004122.2
GZMB	NM_001346011.2	c.244C>G	p.Pro82Ala	missense_variant	3/5		NP_001332940.1
GZMB	NR_144343.2	n.234-265C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GZMB	ENST00000216341.9	c.280C>G	p.Pro94Ala	missense_variant	3/5	1	NM_004131.6	ENSP00000216341	P2
	ENST00000555300.1	n.177+9257G>C		intron_variant, non_coding_transcript_variant		5

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

GnomAD3 exomes AF: 0.210 AC: 47056 AN: 224446 Hom.: 7458 AF XY: 0.214 AC XY: 25855 AN XY: 120664

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 SAS exome AF: 0.298

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

Gnomad4 AFR exome AF: 0.353

Gnomad4 AMR exome AF: 0.139

Gnomad4 ASJ exome AF: 0.252

Gnomad4 EAS exome AF: 0.218

Gnomad4 SAS exome AF: 0.308

Gnomad4 FIN exome AF: 0.182

Gnomad4 NFE exome AF: 0.215

Gnomad4 OTH exome AF: 0.244

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

Gnomad4 AFR AF: 0.348

Gnomad4 AMR AF: 0.199

Gnomad4 ASJ AF: 0.248

Gnomad4 EAS AF: 0.267

Gnomad4 SAS AF: 0.326

Gnomad4 FIN AF: 0.189

Gnomad4 NFE AF: 0.229

Gnomad4 OTH AF: 0.274

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 25, 2017	- -

Computational scores

Source: dbNSFP v4.3

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;T
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.3	.;N
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	3.1	N;N
REVEL	Benign	0.19
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;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

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

Publications

LitVar

Other links and lift over

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