12-6867536-C-T

Variant names:

• chr12-6867536-C-T
• rs200692430
• ENST00000229270.8:c.81C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_000365.6(TPI1):​c.-31C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000177 in 1,607,992 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00077 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: TPI1 NM_000365.6 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.72
• Publications: 1 publications found

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: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 12-6867536-C-T is Benign according to our data. Variant chr12-6867536-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 883746.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000768 (117/152324) while in subpopulation AFR AF = 0.00248 (103/41576). AF 95% confidence interval is 0.00209. There are 0 homozygotes in GnomAd4. There are 44 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPI1	NM_000365.6	c.-31C>T		5_prime_UTR_variant	Exon 1 of 7	ENST00000396705.10	NP_000356.1
TPI1	NM_001159287.1	c.81C>T	p.Asp27Asp	synonymous_variant	Exon 1 of 7		NP_001152759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPI1	ENST00000229270.8	c.81C>T	p.Asp27Asp	synonymous_variant	Exon 1 of 7	1		ENSP00000229270.4
TPI1	ENST00000613953.4	c.81C>T	p.Asp27Asp	synonymous_variant	Exon 1 of 7	1		ENSP00000484435.1
TPI1	ENST00000396705.10	c.-31C>T		5_prime_UTR_variant	Exon 1 of 7	1	NM_000365.6	ENSP00000379933.4

Frequencies

GnomAD3 genomes AF: 0.000762 AC: 116 AN: 152212 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000268 AC: 63 AN: 235252 AF XY: 0.000256

Gnomad AFR exome AF: 0.00308

Gnomad AMR exome AF: 0.000120

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000572

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000476

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000115 AC: 168 AN: 1455668 Hom.: 1 Cov.: 34 AF XY: 0.000111 AC XY: 80 AN XY: 723860

African (AFR) AF: 0.00267 AC: 89 AN: 33302

American (AMR) AF: 0.000206 AC: 9 AN: 43752

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25988

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39510

South Asian (SAS) AF: 0.000269 AC: 23 AN: 85604

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52002

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5748

European-Non Finnish (NFE) AF: 0.0000306 AC: 34 AN: 1109672

Other (OTH) AF: 0.000166 AC: 10 AN: 60090

GnomAD4 genome AF: 0.000768 AC: 117 AN: 152324 Hom.: 0 Cov.: 34 AF XY: 0.000591 AC XY: 44 AN XY: 74486

African (AFR) AF: 0.00248 AC: 103 AN: 41576

American (AMR) AF: 0.000327 AC: 5 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68026

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000965 Hom.: 0

Bravo AF: 0.000945

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Triosephosphate isomerase deficiency Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	2.4
DANN	Benign	0.94
PhyloP100		-1.7
PromoterAI		-0.13	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs200692430; hg19: chr12-6976700;