14-24631185-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_004131.6(GZMB):c.630C>A(p.Asn210Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000982 in 1,613,564 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00095 (10 hom.)
• Consequence: GZMB NM_004131.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.61

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005688399).
• BP6: Variant 14-24631185-G-T is Benign according to our data. Variant chr14-24631185-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 708445.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GZMB	NM_004131.6	c.630C>A	p.Asn210Lys	missense_variant	5/5	ENST00000216341.9
GZMB	NM_001346011.2	c.594C>A	p.Asn198Lys	missense_variant	5/5
GZMB	NR_144343.2	n.524C>A		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GZMB	ENST00000216341.9	c.630C>A	p.Asn210Lys	missense_variant	5/5	1	NM_004131.6	P2
	ENST00000555300.1	n.177+8059G>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00127 AC: 194 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00829

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00167 AC: 419 AN: 251272 Hom.: 2 AF XY: 0.00155 AC XY: 210 AN XY: 135780

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00245

Gnomad SAS exome AF: 0.000555

Gnomad FIN exome AF: 0.0119

Gnomad NFE exome AF: 0.000766

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000952 AC: 1391 AN: 1461244 Hom.: 10 Cov.: 30 AF XY: 0.000915 AC XY: 665 AN XY: 726954

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0105

Gnomad4 SAS exome AF: 0.000499

Gnomad4 FIN exome AF: 0.0111

Gnomad4 NFE exome AF: 0.000234

Gnomad4 OTH exome AF: 0.00123

GnomAD4 genome AF: 0.00127 AC: 193 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.00164 AC XY: 122 AN XY: 74482

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00850

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0106

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000435 Hom.: 0

Bravo AF: 0.000298

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00161 AC: 196

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

May 02, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	0.058
Dann	Benign	0.84
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.46	T;T;T;.;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.0057	T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.0	N;N;.;N;.
REVEL	Benign	0.16
Sift	Benign	0.54	T;T;.;T;.
Sift4G	Benign	0.83	T;T;T;T;T
Polyphen		0.024	.;B;.;.;.
Vest4		0.12
MutPred		0.59		.;Gain of methylation at N210 (P = 0);.;.;.;
MVP		0.73
MPC		0.22
ClinPred		0.0075	T
GERP RS		-6.3
Varity_R		0.14
gMVP		0.47

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: rs74345106; hg19: chr14-25100391;