chr14-24631959-C-T

Variant names:

• chr14-24631959-C-T
• rs747068918
• NM_004131.6:c.499G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004131.6(GZMB):​c.499G>A​(p.Val167Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GZMB NM_004131.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.135
• Publications: 1 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]

GZMH-AS1 (HGNC:58166):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.758

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GZMB	NM_004131.6	MANE Select	c.499G>A	p.Val167Met	missense	Exon 4 of 5	NP_004122.2	P10144
	GZMB	NM_001346011.2		c.463G>A	p.Val155Met	missense	Exon 4 of 5	NP_001332940.1	J3KQ52
	GZMB	NR_144343.2		n.393G>A		non_coding_transcript_exon	Exon 3 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GZMB	ENST00000216341.9	TSL:1 MANE Select	c.499G>A	p.Val167Met	missense	Exon 4 of 5	ENSP00000216341.4	P10144
	GZMB	ENST00000415355.7	TSL:2	c.463G>A	p.Val155Met	missense	Exon 4 of 5	ENSP00000387385.3	J3KQ52
	GZMB	ENST00000859020.1		c.439G>A	p.Val147Met	missense	Exon 4 of 5	ENSP00000529079.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251484 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461866 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111986

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	-0.00060	T
MutationAssessor	Benign	1.7	L
PhyloP100		-0.14
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.98	D
Vest4		0.28
MutPred		0.85		Gain of catalytic residue at V163 (P = 0.0216)
MVP		0.93
MPC		0.62
ClinPred		0.60	D
GERP RS		1.3
Varity_R		0.76
gMVP		0.58
Mutation Taster		=85/15	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: rs747068918; hg19: chr14-25101165; COSMIC: COSV53541269;