14-24607629-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_033423.5(GZMH):​c.322G>A​(p.Asp108Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,612,504 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: 𝑓 0.000020 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

GZMH
NM_033423.5 missense

Scores

7
10
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.24
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.

PM1
In a active_site Charge relay system (size 0) in uniprot entity GRAH_HUMAN
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.854

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GZMHNM_033423.5 linkc.322G>A p.Asp108Asn missense_variant Exon 3 of 5 ENST00000216338.9 NP_219491.1 P20718-1
GZMHNM_001270780.2 linkc.322G>A p.Asp108Asn missense_variant Exon 3 of 5 NP_001257709.1
GZMHNM_001270781.2 linkc.322G>A p.Asp108Asn missense_variant Exon 3 of 4 NP_001257710.1 P20718-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GZMHENST00000216338.9 linkc.322G>A p.Asp108Asn missense_variant Exon 3 of 5 1 NM_033423.5 ENSP00000216338.4 P20718-1
GZMHENST00000557220.6 linkc.204+635G>A intron_variant Intron 2 of 2 1 ENSP00000450576.2 A0A0C4DGJ9

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152192
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000359
AC:
9
AN:
251026
Hom.:
0
AF XY:
0.0000369
AC XY:
5
AN XY:
135638
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000353
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000260
AC:
38
AN:
1460312
Hom.:
0
Cov.:
36
AF XY:
0.0000262
AC XY:
19
AN XY:
726484
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.0000270
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152192
Hom.:
0
Cov.:
34
AF XY:
0.0000269
AC XY:
2
AN XY:
74336
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000565
Hom.:
0
Bravo
AF:
0.0000302
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.000109
EpiControl
AF:
0.0000593

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jun 23, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.322G>A (p.D108N) alteration is located in exon 3 (coding exon 3) of the GZMH gene. This alteration results from a G to A substitution at nucleotide position 322, causing the aspartic acid (D) at amino acid position 108 to be replaced by an asparagine (N). 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
0.72
BayesDel_addAF
Uncertain
0.052
T
BayesDel_noAF
Uncertain
0.060
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.65
D;.
Eigen
Uncertain
0.55
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Uncertain
0.87
D;D
M_CAP
Pathogenic
0.35
D
MetaRNN
Pathogenic
0.85
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.6
H;H
PrimateAI
Benign
0.45
T
PROVEAN
Pathogenic
-4.4
D;D
REVEL
Pathogenic
0.83
Sift
Uncertain
0.018
D;D
Sift4G
Uncertain
0.017
D;D
Polyphen
1.0
D;.
Vest4
0.44
MVP
0.96
MPC
0.52
ClinPred
0.96
D
GERP RS
3.9
Varity_R
0.61
gMVP
0.87

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: rs756399689; hg19: chr14-25076835; API