14-24631084-A-C

Variant names:

• chr14-24631084-A-C
• NM_004131.6:c.731T>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004131.6(GZMB):​c.731T>G​(p.Met244Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GZMB NM_004131.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.92

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.815

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GZMB	NM_004131.6	c.731T>G	p.Met244Arg	missense_variant	Exon 5 of 5	ENST00000216341.9	NP_004122.2
GZMB	NM_001346011.2	c.695T>G	p.Met232Arg	missense_variant	Exon 5 of 5		NP_001332940.1
GZMB	NR_144343.2	n.625T>G		non_coding_transcript_exon_variant	Exon 4 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GZMB	ENST00000216341.9	c.731T>G	p.Met244Arg	missense_variant	Exon 5 of 5	1	NM_004131.6	ENSP00000216341.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461088 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726960

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.68	.;D;T;T;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.82	T;T;T;.;T
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Benign	1.8	.;L;.;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-5.5	D;D;.;D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0060	D;D;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	.;D;.;.;.
Vest4		0.58
MutPred		0.62		.;Gain of solvent accessibility (P = 0.0171);.;.;.;
MVP		0.99
MPC		0.74
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.84
gMVP		0.90

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-25100290;