rs113536847

Variant names:

• chr7-144453614-G-A
• rs113536847
• NM_022445.4:c.663C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_022445.4(TPK1):​c.663C>T​(p.Tyr221Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00327 in 1,613,876 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (9 hom.)
• Consequence: TPK1 NM_022445.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.19
• Publications: 2 publications found

Genes affected

TPK1 (HGNC:17358): (thiamin pyrophosphokinase 1) The protein encoded by this gene functions as a homodimer and catalyzes the conversion of thiamine to thiamine pyrophosphate, a cofactor for some enzymes of the glycolytic and energy production pathways. Defects in this gene are a cause of thiamine metabolism dysfunction syndrome-5. [provided by RefSeq, Apr 2017]

TPK1 Gene-Disease associations (from GenCC):

• childhood encephalopathy due to thiamine pyrophosphokinase deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 7-144453614-G-A is Benign according to our data. Variant chr7-144453614-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.19 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00239 (364/152266) while in subpopulation SAS AF = 0.00395 (19/4814). AF 95% confidence interval is 0.00351. There are 0 homozygotes in GnomAd4. There are 177 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022445.4. 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
	TPK1	NM_022445.4	MANE Select	c.663C>T	p.Tyr221Tyr	synonymous	Exon 9 of 9	NP_071890.2
	TPK1	NM_001350879.1		c.663C>T	p.Tyr221Tyr	synonymous	Exon 9 of 9	NP_001337808.1
	TPK1	NM_001350882.1		c.648C>T	p.Tyr216Tyr	synonymous	Exon 10 of 10	NP_001337811.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPK1	ENST00000360057.7	TSL:1 MANE Select	c.663C>T	p.Tyr221Tyr	synonymous	Exon 9 of 9	ENSP00000353165.3
	TPK1	ENST00000378098.8	TSL:1	n.*419C>T		non_coding_transcript_exon	Exon 10 of 10	ENSP00000367338.4
	TPK1	ENST00000482940.5	TSL:1	n.*694C>T		non_coding_transcript_exon	Exon 12 of 12	ENSP00000449909.1

Frequencies

GnomAD3 genomes AF: 0.00239 AC: 364 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00390

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00253 AC: 636 AN: 251394 AF XY: 0.00291

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.00361

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00336 AC: 4913 AN: 1461610 Hom.: 9 Cov.: 30 AF XY: 0.00339 AC XY: 2465 AN XY: 727124

African (AFR) AF: 0.000478 AC: 16 AN: 33460

American (AMR) AF: 0.00127 AC: 57 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00203 AC: 53 AN: 26128

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39692

South Asian (SAS) AF: 0.00493 AC: 425 AN: 86242

European-Finnish (FIN) AF: 0.000393 AC: 21 AN: 53418

Middle Eastern (MID) AF: 0.00329 AC: 19 AN: 5768

European-Non Finnish (NFE) AF: 0.00368 AC: 4092 AN: 1111802

Other (OTH) AF: 0.00376 AC: 227 AN: 60384

GnomAD4 genome AF: 0.00239 AC: 364 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.00238 AC XY: 177 AN XY: 74444

African (AFR) AF: 0.000746 AC: 31 AN: 41554

American (AMR) AF: 0.00229 AC: 35 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00395 AC: 19 AN: 4814

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00390 AC: 265 AN: 68022

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.00320 Hom.: 0

Bravo AF: 0.00221

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00365

EpiControl AF: 0.00486

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Childhood encephalopathy due to thiamine pyrophosphokinase deficiency (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	2.0
DANN	Benign	0.85
PhyloP100		-2.2
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: rs113536847; hg19: chr7-144150707; COSMIC: COSV63641482; COSMIC: COSV63641482;