rs1320821

Variant names:

• chr7-144770627-G-A
• rs1320821
• NM_022445.4:c.44-4676C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022445.4(TPK1):​c.44-4676C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.19 in 151,838 control chromosomes in the GnomAD database, including 3,039 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.19 (3039 hom., cov: 32)
• Consequence: TPK1 NM_022445.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.512
• Publications: 4 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, PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

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.44-4676C>T		intron	N/A	NP_071890.2
	TPK1	NM_001350879.1		c.44-4676C>T		intron	N/A	NP_001337808.1	Q9H3S4-1
	TPK1	NM_001350881.1		c.44-4676C>T		intron	N/A	NP_001337810.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPK1	ENST00000360057.7	TSL:1 MANE Select	c.44-4676C>T		intron	N/A	ENSP00000353165.3	Q9H3S4-1
	TPK1	ENST00000378098.8	TSL:1	n.44-4676C>T		intron	N/A	ENSP00000367338.4	F8WCM7
	TPK1	ENST00000889991.1		c.44-4676C>T		intron	N/A	ENSP00000560050.1

Frequencies

GnomAD3 genomes AF: 0.190 AC: 28870 AN: 151718 Hom.: 3044 Cov.: 32

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.0956

Gnomad AMR AF: 0.204

Gnomad ASJ AF: 0.280

Gnomad EAS AF: 0.187

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.224

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.226

Gnomad OTH AF: 0.248

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.190 AC: 28866 AN: 151838 Hom.: 3039 Cov.: 32 AF XY: 0.190 AC XY: 14097 AN XY: 74206

African (AFR) AF: 0.108 AC: 4490 AN: 41404

American (AMR) AF: 0.203 AC: 3094 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.280 AC: 972 AN: 3472

East Asian (EAS) AF: 0.186 AC: 965 AN: 5176

South Asian (SAS) AF: 0.189 AC: 908 AN: 4814

European-Finnish (FIN) AF: 0.224 AC: 2353 AN: 10526

Middle Eastern (MID) AF: 0.479 AC: 139 AN: 290

European-Non Finnish (NFE) AF: 0.226 AC: 15339 AN: 67912

Other (OTH) AF: 0.246 AC: 519 AN: 2108

Alfa AF: 0.209 Hom.: 1767

Bravo AF: 0.186

Asia WGS AF: 0.191 AC: 663 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.19
DANN	Benign	0.58
PhyloP100		-0.51
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1320821;

hg19: chr7-144467720;