12-6867524-A-G

Variant names:

• chr12-6867524-A-G
• rs1800200
• ENST00000229270.8:c.69A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001159287.1(TPI1):​c.69A>G​(p.Arg23Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0301 in 1,599,278 control chromosomes in the GnomAD database, including 4,932 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.095 (1764 hom., cov: 34)
  • Exomes 𝑓: 0.023 (3168 hom.)
• Consequence: TPI1 NM_001159287.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.87
• Publications: 12 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: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 12-6867524-A-G is Benign according to our data. Variant chr12-6867524-A-G is described in ClinVar as Benign. ClinVar VariationId is 369027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.87 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001159287.1. 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.69A>G	p.Arg23Arg	synonymous	Exon 1 of 7	NP_001152759.1	P60174-3
	TPI1	NM_000365.6	MANE Select	c.-43A>G		upstream_gene	N/A	NP_000356.1	P60174-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPI1	ENST00000229270.8	TSL:1	c.69A>G	p.Arg23Arg	synonymous	Exon 1 of 7	ENSP00000229270.4	P60174-3
	TPI1	ENST00000613953.4	TSL:1	c.69A>G	p.Arg23Arg	synonymous	Exon 1 of 7	ENSP00000484435.1	P60174-3
	TPI1	ENST00000934760.1		c.-43A>G		5_prime_UTR	Exon 1 of 7	ENSP00000604819.1

Frequencies

GnomAD3 genomes AF: 0.0944 AC: 14357 AN: 152040 Hom.: 1741 Cov.: 34

Gnomad AFR AF: 0.260

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.0205

Gnomad EAS AF: 0.256

Gnomad SAS AF: 0.0126

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.00468

Gnomad OTH AF: 0.0927

GnomAD2 exomes AF: 0.0586 AC: 12998 AN: 221854 AF XY: 0.0479

Gnomad AFR exome AF: 0.263

Gnomad AMR exome AF: 0.134

Gnomad ASJ exome AF: 0.0219

Gnomad EAS exome AF: 0.268

Gnomad FIN exome AF: 0.000401

Gnomad NFE exome AF: 0.00443

Gnomad OTH exome AF: 0.0359

GnomAD4 exome AF: 0.0233 AC: 33782 AN: 1447126 Hom.: 3168 Cov.: 34 AF XY: 0.0217 AC XY: 15611 AN XY: 718882

African (AFR) AF: 0.277 AC: 9184 AN: 33098

American (AMR) AF: 0.127 AC: 5370 AN: 42200

Ashkenazi Jewish (ASJ) AF: 0.0236 AC: 609 AN: 25820

East Asian (EAS) AF: 0.260 AC: 10202 AN: 39194

South Asian (SAS) AF: 0.0102 AC: 864 AN: 84738

European-Finnish (FIN) AF: 0.000467 AC: 24 AN: 51408

Middle Eastern (MID) AF: 0.0416 AC: 238 AN: 5720

European-Non Finnish (NFE) AF: 0.00443 AC: 4898 AN: 1105142

Other (OTH) AF: 0.0400 AC: 2393 AN: 59806

GnomAD4 genome AF: 0.0948 AC: 14424 AN: 152152 Hom.: 1764 Cov.: 34 AF XY: 0.0944 AC XY: 7022 AN XY: 74402

African (AFR) AF: 0.261 AC: 10836 AN: 41492

American (AMR) AF: 0.105 AC: 1607 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0205 AC: 71 AN: 3466

East Asian (EAS) AF: 0.256 AC: 1319 AN: 5150

South Asian (SAS) AF: 0.0124 AC: 60 AN: 4820

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10624

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.00468 AC: 318 AN: 67990

Other (OTH) AF: 0.0936 AC: 197 AN: 2104

Alfa AF: 0.0322 Hom.: 306

Bravo AF: 0.111

Asia WGS AF: 0.106 AC: 367 AN: 3470

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Triosephosphate isomerase deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	17
DANN	Benign	0.85
PhyloP100		2.9
PromoterAI		0.16	Neutral
Mutation Taster		=99/1	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs1800200; hg19: chr12-6976688;