14-24607725-C-T

Variant names:

• chr14-24607725-C-T
• rs527360788
• NM_033423.5:c.226G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_033423.5(GZMH):​c.226G>A​(p.Ala76Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,746 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A76S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: GZMH NM_033423.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.73
• Publications: 0 publications found

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]

GZMH-AS1 (HGNC:58166):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.755

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033423.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GZMH	NM_033423.5	MANE Select	c.226G>A	p.Ala76Thr	missense	Exon 3 of 5	NP_219491.1	P20718-1
	GZMH	NM_001270780.2		c.226G>A	p.Ala76Thr	missense	Exon 3 of 5	NP_001257709.1
	GZMH	NM_001270781.2		c.226G>A	p.Ala76Thr	missense	Exon 3 of 4	NP_001257710.1	P20718-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GZMH	ENST00000216338.9	TSL:1 MANE Select	c.226G>A	p.Ala76Thr	missense	Exon 3 of 5	ENSP00000216338.4	P20718-1
	GZMH	ENST00000382548.4	TSL:1	c.226G>A	p.Ala76Thr	missense	Exon 3 of 4	ENSP00000371988.4	P20718-2
	GZMH	ENST00000557220.6	TSL:1	c.204+539G>A		intron	N/A	ENSP00000450576.2	A0A0C4DGJ9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251426 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000684 AC: 10 AN: 1461746 Hom.: 0 Cov.: 34 AF XY: 0.00000688 AC XY: 5 AN XY: 727176

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111910

Other (OTH) AF: 0.0000331 AC: 2 AN: 60380

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.072	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.092	D
MutationAssessor	Benign	0.91	L
PhyloP100		3.7
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.46
MutPred		0.71		Gain of glycosylation at A76 (P = 0.0258)
MVP		0.79
MPC		0.53
ClinPred		0.95	D
GERP RS		4.7
Varity_R		0.77
gMVP		0.57
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

dbSNP: rs527360788; hg19: chr14-25076931;