dbSNP rs17786733: TPO:n.180+32755T>A (chr2-1407157-T-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000497517.6(TPO):n.180+32755T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.398 in 152,044 control chromosomes in the GnomAD database, including 12,134 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 0.40 ( 12134 hom., cov: 33)

Consequence

TPO
ENST00000497517.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.336

Publications

4 publications found

Variant links:

Genes affected

TPO (HGNC:12015): (thyroid peroxidase) This gene encodes a membrane-bound glycoprotein. The encoded protein acts as an enzyme and plays a central role in thyroid gland function. The protein functions in the iodination of tyrosine residues in thyroglobulin and phenoxy-ester formation between pairs of iodinated tyrosines to generate the thyroid hormones, thyroxine and triiodothyronine. Mutations in this gene are associated with several disorders of thyroid hormonogenesis, including congenital hypothyroidism, congenital goiter, and thyroid hormone organification defect IIA. Multiple transcript variants encoding distinct isoforms have been identified for this gene, but the full-length nature of some variants has not been determined. [provided by RefSeq, May 2011]

TPO Gene-Disease associations (from GenCC):

thyroid dyshormonogenesis 2A
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
familial thyroid dyshormonogenesis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TPO links:

ENSG00000231482 (HGNC:):

ENSG00000231482 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.479 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein
TPO	XM_024453089.2 link	c.-417+101T>A	intron_variant	Intron 2 of 17	XP_024308857.1
TPO	XM_047445652.1 link	c.-417+101T>A	intron_variant	Intron 3 of 18	XP_047301608.1
TPO	XM_047445653.1 link	c.-417+101T>A	intron_variant	Intron 3 of 18	XP_047301609.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL
TPO	ENST00000497517.6 link	n.180+32755T>A	intron_variant	Intron 1 of 5	1
TPO	ENST00000650224.1 link	n.497+101T>A	intron_variant	Intron 3 of 3
ENSG00000231482	ENST00000650512.1 link	n.865+2372A>T	intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.398

AC:

60538

AN:

151926

Hom.:

12125

Cov.:

show subpopulations

Gnomad AFR

AF:

0.360

Gnomad AMI

AF:

0.344

Gnomad AMR

AF:

0.487

Gnomad ASJ

AF:

0.456

Gnomad EAS

AF:

0.305

Gnomad SAS

AF:

0.458

Gnomad FIN

AF:

0.426

Gnomad MID

AF:

0.361

Gnomad NFE

AF:

0.399

Gnomad OTH

AF:

0.393

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

GnomAD4 genome

AF:

0.398

AC:

60576

AN:

152044

Hom.:

12134

Cov.:

AF XY:

0.399

AC XY:

29626

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.360

AC:

14927

AN:

41476

American (AMR)

AF:

0.488

AC:

7466

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.456

AC:

1581

AN:

3468

East Asian (EAS)

AF:

0.304

AC:

1573

AN:

5168

South Asian (SAS)

AF:

0.456

AC:

2197

AN:

4818

European-Finnish (FIN)

AF:

0.426

AC:

4495

AN:

10550

Middle Eastern (MID)

AF:

0.361

AC:

106

AN:

294

European-Non Finnish (NFE)

AF:

0.399

AC:

27089

AN:

67968

Other (OTH)

AF:

0.393

AC:

830

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1883

3766

5648

7531

9414

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

578

1156

1734

2312

2890

<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:

0.401

Hom.:

1535

Bravo

AF:

0.400

Asia WGS

AF:

0.415

AC:

1443

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

2.1

(source)

DANN

Benign

0.45

PhyloP100

0.34

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over