Genetic Variant ENST00000229270.8:c.66G>A (chr12-6867521-G-A) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4BP6_Very_StrongBP7BA1

The ENST00000229270.8(TPI1):c.66G>A(p.Pro22Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00862 in 1,596,292 control chromosomes in the GnomAD database, including 486 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.032 ( 243 hom., cov: 34)

Exomes 𝑓: 0.0061 ( 243 hom. )

Consequence

TPI1
ENST00000229270.8 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.76

Publications

7 publications found

Variant links:

Genes affected

TPI1 (HGNC:12009): (triosephosphate isomerase 1) This gene encodes an enzyme, consisting of two identical proteins, which catalyzes the isomerization of glyceraldehydes 3-phosphate (G3P) and dihydroxy-acetone phosphate (DHAP) in glycolysis and gluconeogenesis. Mutations in this gene are associated with triosephosphate isomerase deficiency. Pseudogenes have been identified on chromosomes 1, 4, 6 and 7. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2009]

TPI1 Gene-Disease associations (from GenCC):

triosephosphate isomerase deficiency
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)

TPI1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.16).

BP6

Variant 12-6867521-G-A is Benign according to our data. Variant chr12-6867521-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 369026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.76 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000229270.8. 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
	TPI1	NM_001159287.1		c.66G>A	p.Pro22Pro	synonymous	Exon 1 of 7	NP_001152759.1	P60174-3
	TPI1	NM_000365.6	MANE Select	c.-46G>A		upstream_gene	N/A	NP_000356.1	P60174-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TPI1	ENST00000229270.8	TSL:1	c.66G>A	p.Pro22Pro	synonymous	Exon 1 of 7	ENSP00000229270.4	P60174-3
TPI1	ENST00000613953.4	TSL:1	c.66G>A	p.Pro22Pro	synonymous	Exon 1 of 7	ENSP00000484435.1	P60174-3
TPI1	ENST00000934760.1		c.-46G>A		5_prime_UTR	Exon 1 of 7	ENSP00000604819.1

Frequencies

GnomAD3 genomes

AF:

0.0323

AC:

4918

AN:

152146

Hom.:

242

Cov.:

show subpopulations

Gnomad AFR

AF:

0.107

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0137

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00290

Gnomad OTH

AF:

0.0268

GnomAD2 exomes

AF:

0.00844

AC:

1830

AN:

216926

AF XY:

0.00713

show subpopulations

Gnomad AFR exome

AF:

0.105

Gnomad AMR exome

AF:

0.00701

Gnomad ASJ exome

AF:

0.00246

Gnomad EAS exome

AF:

0.000122

Gnomad FIN exome

AF:

0.000358

Gnomad NFE exome

AF:

0.00279

Gnomad OTH exome

AF:

0.00718

GnomAD4 exome

AF:

0.00612

AC:

8839

AN:

1444032

Hom.:

243

Cov.:

AF XY:

0.00581

AC XY:

4167

AN XY:

717010

show subpopulations

African (AFR)

AF:

0.118

AC:

3910

AN:

33050

American (AMR)

AF:

0.00773

AC:

323

AN:

41766

Ashkenazi Jewish (ASJ)

AF:

0.00334

AC:

AN:

25762

East Asian (EAS)

AF:

0.000179

AC:

AN:

39044

South Asian (SAS)

AF:

0.00156

AC:

132

AN:

84416

European-Finnish (FIN)

AF:

0.000469

AC:

AN:

51138

Middle Eastern (MID)

AF:

0.0228

AC:

130

AN:

5704

European-Non Finnish (NFE)

AF:

0.00324

AC:

3580

AN:

1103484

Other (OTH)

AF:

0.0108

AC:

647

AN:

59668

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

466

932

1398

1864

2330

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

218

436

654

872

1090

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0324

AC:

4928

AN:

152260

Hom.:

243

Cov.:

AF XY:

0.0320

AC XY:

2383

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.107

AC:

4444

AN:

41534

American (AMR)

AF:

0.0136

AC:

208

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5166

South Asian (SAS)

AF:

0.00103

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00290

AC:

197

AN:

68000

Other (OTH)

AF:

0.0265

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

225

450

674

899

1124

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0151

Hom.:

Bravo

AF:

0.0356

Asia WGS

AF:

0.00955

AC:

AN:

3470

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Triosephosphate isomerase deficiency (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Benign

0.97

PhyloP100

1.8

PromoterAI

-0.25

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over