14-24607191-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_033423.5(GZMH):​c.555G>T​(p.Glu185Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,976 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

GZMH
NM_033423.5 missense

Scores

2
6
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.918
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 Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GZMHNM_033423.5 linkc.555G>T p.Glu185Asp missense_variant Exon 4 of 5 ENST00000216338.9 NP_219491.1 P20718-1
GZMHNM_001270780.2 linkc.405+150G>T intron_variant Intron 4 of 4 NP_001257709.1
GZMHNM_001270781.2 linkc.339+421G>T intron_variant Intron 3 of 3 NP_001257710.1 P20718-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GZMHENST00000216338.9 linkc.555G>T p.Glu185Asp missense_variant Exon 4 of 5 1 NM_033423.5 ENSP00000216338.4 P20718-1
GZMHENST00000557220.6 linkc.205-445G>T intron_variant Intron 2 of 2 1 ENSP00000450576.2 A0A0C4DGJ9

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152224
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250760
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135558
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461752
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
727176
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
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
AF:
0.0000131
AC:
2
AN:
152224
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74378
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Sep 03, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.555G>T (p.E185D) alteration is located in exon 4 (coding exon 4) of the GZMH gene. This alteration results from a G to T substitution at nucleotide position 555, causing the glutamic acid (E) at amino acid position 185 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
0.67
BayesDel_addAF
Benign
-0.029
T
BayesDel_noAF
Benign
-0.20
CADD
Benign
19
DANN
Uncertain
1.0
DEOGEN2
Benign
0.34
T
Eigen
Benign
-0.18
Eigen_PC
Benign
-0.22
FATHMM_MKL
Benign
0.50
N
LIST_S2
Uncertain
0.91
D
M_CAP
Uncertain
0.11
D
MetaRNN
Uncertain
0.56
D
MetaSVM
Uncertain
0.013
D
MutationAssessor
Benign
-0.035
N
PrimateAI
Benign
0.28
T
PROVEAN
Benign
-2.3
N
REVEL
Uncertain
0.42
Sift
Pathogenic
0.0
D
Sift4G
Benign
0.094
T
Polyphen
0.81
P
Vest4
0.23
MutPred
0.80
Gain of sheet (P = 0.0827);
MVP
0.89
MPC
0.40
ClinPred
0.62
D
GERP RS
2.9
Varity_R
0.86
gMVP
0.51

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs745934038; hg19: chr14-25076397; API