3-53228090-G-T

Variant names:

• chr3-53228090-G-T
• rs200391494
• NM_001064.4:c.1539C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001064.4(TKT):​c.1539C>A​(p.His513Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,110 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TKT NM_001064.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.09
• Publications: 0 publications found

Genes affected

TKT (HGNC:11834): (transketolase) This gene encodes a thiamine-dependent enzyme which plays a role in the channeling of excess sugar phosphates to glycolysis in the pentose phosphate pathway. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Apr 2012]

TKT Gene-Disease associations (from GenCC):

• transketolase deficiency

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 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
TKT	NM_001064.4	c.1539C>A	p.His513Gln	missense_variant	Exon 12 of 14	ENST00000462138.6	NP_001055.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TKT	ENST00000462138.6	c.1539C>A	p.His513Gln	missense_variant	Exon 12 of 14	1	NM_001064.4	ENSP00000417773.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461110 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726870

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44722

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: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5162

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111980

Other (OTH) AF: 0.00 AC: 0 AN: 60326

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	0.43
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.82	D;D;.;T
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.86	.;D;D;D
M_CAP	Uncertain	0.086	D
MetaRNN	Uncertain	0.52	D;D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Benign	1.8	L;L;.;.
PhyloP100		-1.1
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.3	D;D;D;.
REVEL	Uncertain	0.57
Sift	Uncertain	0.0090	D;D;D;.
Sift4G	Uncertain	0.017	D;D;D;T
Polyphen		0.98	D;D;.;.
Vest4		0.57
MutPred		0.74		Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);.;.;
MVP		0.66
MPC		0.64
ClinPred		0.98	D
GERP RS		-11
Varity_R		0.81
gMVP		0.84
Mutation Taster		=8/92	disease causing

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: rs200391494; hg19: chr3-53262106;