rs142875748

Variant names:

• chr14-24631158-A-G
• rs142875748
• NM_004131.6:c.657T>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_004131.6(GZMB):​c.657T>C​(p.Tyr219Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 1,611,976 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (9 hom.)
• Consequence: GZMB NM_004131.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.515
• Publications: 2 publications found

Genes affected

GZMB (HGNC:4709): (granzyme B) This gene encodes a member of the granzyme subfamily of proteins, part of the peptidase S1 family of serine proteases. The encoded preproprotein is secreted by natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) and proteolytically processed to generate the active protease, which induces target cell apoptosis. This protein also processes cytokines and degrades extracellular matrix proteins, and these roles are implicated in chronic inflammation and wound healing. Expression of this gene may be elevated in human patients with cardiac fibrosis. [provided by RefSeq, Sep 2016]

GZMH-AS1 (HGNC:58166):

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 14-24631158-A-G is Benign according to our data. Variant chr14-24631158-A-G is described in ClinVar as Benign. ClinVar VariationId is 774488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.515 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004131.6. 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
	GZMB	NM_004131.6	MANE Select	c.657T>C	p.Tyr219Tyr	synonymous	Exon 5 of 5	NP_004122.2	P10144
	GZMB	NM_001346011.2		c.621T>C	p.Tyr207Tyr	synonymous	Exon 5 of 5	NP_001332940.1	J3KQ52
	GZMB	NR_144343.2		n.551T>C		non_coding_transcript_exon	Exon 4 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GZMB	ENST00000216341.9	TSL:1 MANE Select	c.657T>C	p.Tyr219Tyr	synonymous	Exon 5 of 5	ENSP00000216341.4	P10144
	GZMB	ENST00000415355.7	TSL:2	c.621T>C	p.Tyr207Tyr	synonymous	Exon 5 of 5	ENSP00000387385.3	J3KQ52
	GZMB	ENST00000859020.1		c.597T>C	p.Tyr199Tyr	synonymous	Exon 5 of 5	ENSP00000529079.1

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 294 AN: 152162 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00285

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00188

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00166 AC: 418 AN: 251378 AF XY: 0.00195

Gnomad AFR exome AF: 0.00344

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00204

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00189 AC: 2757 AN: 1459696 Hom.: 9 Cov.: 30 AF XY: 0.00198 AC XY: 1436 AN XY: 726318

African (AFR) AF: 0.00338 AC: 113 AN: 33424

American (AMR) AF: 0.000693 AC: 31 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00310 AC: 267 AN: 86214

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53420

Middle Eastern (MID) AF: 0.0111 AC: 64 AN: 5746

European-Non Finnish (NFE) AF: 0.00193 AC: 2143 AN: 1110040

Other (OTH) AF: 0.00224 AC: 135 AN: 60328

GnomAD4 genome AF: 0.00197 AC: 300 AN: 152280 Hom.: 1 Cov.: 32 AF XY: 0.00188 AC XY: 140 AN XY: 74458

African (AFR) AF: 0.00296 AC: 123 AN: 41556

American (AMR) AF: 0.00183 AC: 28 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00188 AC: 128 AN: 68022

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00216 Hom.: 0

Bravo AF: 0.00205

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00251

EpiControl AF: 0.00267

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	1.5
DANN	Benign	0.60
PhyloP100		0.52
Mutation Taster		=100/0	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: rs142875748; hg19: chr14-25100364;