rs748550470

Variant names:

• chr7-143264644-C-T
• rs748550470
• NM_015917.3:c.251C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_015917.3(GSTK1):​c.251C>T​(p.Pro84Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,613,960 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 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: GSTK1 NM_015917.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.51
• Publications: 0 publications found

Genes affected

GSTK1 (HGNC:16906): (glutathione S-transferase kappa 1) This gene encodes a member of the kappa class of the glutathione transferase superfamily of enzymes that function in cellular detoxification. The encoded protein is localized to the peroxisome and catalyzes the conjugation of glutathione to a wide range of hydrophobic substates facilitating the removal of these compounds from cells. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Jan 2009]

TMEM139-AS1 (HGNC:40988): (TMEM139 antisense RNA 1)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015917.3. 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
	GSTK1	NM_015917.3	MANE Select	c.251C>T	p.Pro84Leu	missense	Exon 3 of 8	NP_057001.1	Q9Y2Q3-1
	GSTK1	NM_001143679.2		c.251C>T	p.Pro84Leu	missense	Exon 3 of 7	NP_001137151.1	Q9Y2Q3-2
	GSTK1	NM_001143680.2		c.251C>T	p.Pro84Leu	missense	Exon 3 of 7	NP_001137152.1	Q9Y2Q3-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSTK1	ENST00000358406.10	TSL:1 MANE Select	c.251C>T	p.Pro84Leu	missense	Exon 3 of 8	ENSP00000351181.5	Q9Y2Q3-1
	GSTK1	ENST00000479303.1	TSL:1	c.251C>T	p.Pro84Leu	missense	Exon 3 of 7	ENSP00000431049.1	Q9Y2Q3-2
	GSTK1	ENST00000881234.1		c.251C>T	p.Pro84Leu	missense	Exon 3 of 7	ENSP00000551293.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251460 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461810 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727212

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000268 AC: 7 AN: 26132

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111958

Other (OTH) AF: 0.000132 AC: 8 AN: 60388

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74318

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000474 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.017	T
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.076	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		4.5
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-8.0	D
REVEL	Uncertain	0.33
Sift	Benign	0.041	D
Sift4G	Benign	0.26	T
Polyphen		1.0	D
Vest4		0.55
MutPred		0.84		Gain of catalytic residue at P84 (P = 0.011)
MVP		0.65
MPC		1.1
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.78
gMVP		0.93
Mutation Taster		=58/42	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: rs748550470; hg19: chr7-142961737;