14-24606703-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_033423.5(GZMH):​c.641G>A​(p.Gly214Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)

Consequence

GZMH
NM_033423.5 missense

Scores

12
6
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.73
Variant links:
Genes affected
GZMH (HGNC:4710): (granzyme H) This gene encodes a member of the peptidase S1 family of serine proteases. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate a chymotrypsin-like protease. This protein is reported to be constitutively expressed in the NK (natural killer) cells of the immune system and may play a role in the cytotoxic arm of the innate immune response by inducing target cell death and by directly cleaving substrates in pathogen-infected cells. This gene is present in a gene cluster with another member of the granzyme subfamily on chromosome 14. [provided by RefSeq, Nov 2015]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.995

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GZMHNM_033423.5 linkc.641G>A p.Gly214Asp missense_variant Exon 5 of 5 ENST00000216338.9 NP_219491.1 P20718-1
GZMHNM_001270780.2 linkc.449G>A p.Gly150Asp missense_variant Exon 5 of 5 NP_001257709.1
GZMHNM_001270781.2 linkc.383G>A p.Gly128Asp missense_variant Exon 4 of 4 NP_001257710.1 P20718-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GZMHENST00000216338.9 linkc.641G>A p.Gly214Asp missense_variant Exon 5 of 5 1 NM_033423.5 ENSP00000216338.4 P20718-1
GZMHENST00000557220.6 linkc.248G>A p.Gly83Asp missense_variant Exon 3 of 3 1 ENSP00000450576.2 A0A0C4DGJ9

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 11, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.641G>A (p.G214D) alteration is located in exon 5 (coding exon 5) of the GZMH gene. This alteration results from a G to A substitution at nucleotide position 641, causing the glycine (G) at amino acid position 214 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.90
BayesDel_addAF
Pathogenic
0.53
D
BayesDel_noAF
Pathogenic
0.52
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.87
D;.;.
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.41
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.96
D;D;D
M_CAP
Pathogenic
0.77
D
MetaRNN
Pathogenic
1.0
D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
4.6
H;.;.
PrimateAI
Uncertain
0.53
T
PROVEAN
Pathogenic
-6.9
D;.;D
REVEL
Pathogenic
0.89
Sift
Pathogenic
0.0
D;.;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
D;.;.
Vest4
0.90
MutPred
0.94
Gain of catalytic residue at G214 (P = 0.0545);.;.;
MVP
0.95
MPC
0.61
ClinPred
0.98
D
GERP RS
4.5
Varity_R
0.93
gMVP
0.91

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: chr14-25075909; API