7-143268144-A-T

Variant names:

• chr7-143268144-A-T
• rs1800935743
• NM_015917.3:c.591A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015917.3(GSTK1):​c.591A>T​(p.Leu197Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GSTK1 NM_015917.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.27
• 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_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06451559).

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.591A>T	p.Leu197Phe	missense	Exon 7 of 8	NP_057001.1	Q9Y2Q3-1
	GSTK1	NM_001143679.2		c.759A>T	p.Leu253Phe	missense	Exon 6 of 7	NP_001137151.1	Q9Y2Q3-2
	GSTK1	NM_001143680.2		c.555A>T	p.Leu185Phe	missense	Exon 6 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.591A>T	p.Leu197Phe	missense	Exon 7 of 8	ENSP00000351181.5	Q9Y2Q3-1
	GSTK1	ENST00000479303.1	TSL:1	c.759A>T	p.Leu253Phe	missense	Exon 6 of 7	ENSP00000431049.1	Q9Y2Q3-2
	GSTK1	ENST00000881234.1		c.759A>T	p.Leu253Phe	missense	Exon 6 of 7	ENSP00000551293.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461810 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727214

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111970

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152082 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74290

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41408

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2086

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

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	Benign	0.21
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.061
DANN	Benign	0.86
DEOGEN2	Benign	0.063	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.065	N
PhyloP100		-1.3
PrimateAI	Benign	0.41	T
PROVEAN	Benign	2.8	N
REVEL	Benign	0.084
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0060	B
Vest4		0.20
MutPred		0.77		Gain of sheet (P = 0.1539)
MVP		0.030
MPC		0.72
ClinPred		0.58	D
GERP RS		-2.2
Varity_R		0.27
gMVP		0.85
Mutation Taster		=59/41	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: rs1800935743; hg19: chr7-142965237;