chr22-24220041-C-T

Variant names:

• chr22-24220041-C-T
• NM_004121.5:c.1690G>A

Variant summary

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

The NM_004121.5(GGT5):​c.1690G>A​(p.Val564Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GGT5 NM_004121.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.23

Genes affected

GGT5 (HGNC:4260): (gamma-glutamyltransferase 5) This gene is a member of the gamma-glutamyl transpeptidase gene family, and some reports indicate that it is capable of cleaving the gamma-glutamyl moiety of glutathione. The protein encoded by this gene is synthesized as a single, catalytically-inactive polypeptide, that is processed post-transcriptionally to form a heavy and light subunit, with the catalytic activity contained within the small subunit. The encoded enzyme is able to convert leukotriene C4 to leukotriene D4, but appears to have distinct substrate specificity compared to gamma-glutamyl transpeptidase. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2014]

ACMG classification

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
GGT5	NM_004121.5	c.1690G>A	p.Val564Met	missense_variant	Exon 12 of 12	ENST00000327365.10	NP_004112.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GGT5	ENST00000327365.10	c.1690G>A	p.Val564Met	missense_variant	Exon 12 of 12	1	NM_004121.5	ENSP00000330080.4
GGT5	ENST00000398292.3	c.1693G>A	p.Val565Met	missense_variant	Exon 12 of 12	1		ENSP00000381340.3
GGT5	ENST00000263112.11	c.1594G>A	p.Val532Met	missense_variant	Exon 11 of 11	1		ENSP00000263112.7
GGT5	ENST00000425408.5	c.589G>A	p.Val197Met	missense_variant	Exon 6 of 6	5		ENSP00000402917.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1690G>A (p.V564M) alteration is located in exon 12 (coding exon 12) of the GGT5 gene. This alteration results from a G to A substitution at nucleotide position 1690, causing the valine (V) at amino acid position 564 to be replaced by a methionine (M). 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	Uncertain	0.50
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	.;T;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.24	N
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.65	D;D;D
MetaSVM	Benign	-0.83	T
MutationAssessor	Pathogenic	3.2	.;M;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Benign	0.21
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.47
MutPred		0.72		.;Gain of catalytic residue at V560 (P = 0.0208);.;
MVP		0.32
MPC		0.73
ClinPred		0.95	D
GERP RS		2.6
Varity_R		0.37
gMVP		0.80

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-24616009;