14-24606610-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_033423.5(GZMH):​c.734G>A​(p.Arg245His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000825 in 1,612,872 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R245C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000081 ( 1 hom. )

Consequence

GZMH
NM_033423.5 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.96
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_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.010121375).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GZMHNM_033423.5 linkc.734G>A p.Arg245His missense_variant Exon 5 of 5 ENST00000216338.9 NP_219491.1 P20718-1
GZMHNM_001270780.2 linkc.542G>A p.Arg181His missense_variant Exon 5 of 5 NP_001257709.1
GZMHNM_001270781.2 linkc.476G>A p.Arg159His 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.734G>A p.Arg245His missense_variant Exon 5 of 5 1 NM_033423.5 ENSP00000216338.4 P20718-1
GZMHENST00000557220.6 linkc.341G>A p.Arg114His missense_variant Exon 3 of 3 1 ENSP00000450576.2 A0A0C4DGJ9

Frequencies

GnomAD3 genomes
AF:
0.0000920
AC:
14
AN:
152202
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00115
Gnomad EAS
AF:
0.000578
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000152
AC:
38
AN:
249972
Hom.:
1
AF XY:
0.000126
AC XY:
17
AN XY:
135084
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00241
Gnomad EAS exome
AF:
0.000600
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000265
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000815
AC:
119
AN:
1460552
Hom.:
1
Cov.:
31
AF XY:
0.0000881
AC XY:
64
AN XY:
726656
show subpopulations
Gnomad4 AFR exome
AF:
0.0000300
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00208
Gnomad4 EAS exome
AF:
0.000403
Gnomad4 SAS exome
AF:
0.0000349
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000333
Gnomad4 OTH exome
AF:
0.000133
GnomAD4 genome
AF:
0.0000919
AC:
14
AN:
152320
Hom.:
0
Cov.:
32
AF XY:
0.0000806
AC XY:
6
AN XY:
74476
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00115
Gnomad4 EAS
AF:
0.000579
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000197
Hom.:
0
Bravo
AF:
0.000102
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000115
AC:
14
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Dec 08, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.734G>A (p.R245H) 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 734, causing the arginine (R) at amino acid position 245 to be replaced by a histidine (H). 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
Benign
0.10
BayesDel_addAF
Benign
-0.38
T
BayesDel_noAF
Benign
-0.43
CADD
Benign
0.093
DANN
Benign
0.72
DEOGEN2
Benign
0.074
T;.;.
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.0044
N
LIST_S2
Benign
0.65
T;T;T
M_CAP
Benign
0.019
T
MetaRNN
Benign
0.010
T;T;T
MetaSVM
Benign
-0.70
T
MutationAssessor
Benign
0.55
N;.;.
PrimateAI
Benign
0.19
T
PROVEAN
Benign
-1.5
N;.;N
REVEL
Benign
0.17
Sift
Benign
0.14
T;.;T
Sift4G
Benign
0.20
T;T;T
Polyphen
0.025
B;.;.
Vest4
0.065
MVP
0.74
MPC
0.14
ClinPred
0.013
T
GERP RS
-4.0
Varity_R
0.077
gMVP
0.36

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

LitVar

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

Other links and lift over

dbSNP: rs140139906; hg19: chr14-25075816; COSMIC: COSV53537838; API