dbSNP rs877153: TPO:n.180+7415A>G (chr2-1381817-A-G) – 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+7415A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0579 in 152,182 control chromosomes in the GnomAD database, including 672 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 0.058 ( 672 hom., cov: 32)

Consequence

TPO
ENST00000497517.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.34

Publications

1 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=-0.9).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.291 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein
TPO	XM_024453089.2 link	c.-481+7415A>G	intron_variant	Intron 1 of 17	XP_024308857.1
TPO	XM_047445652.1 link	c.-1392+7415A>G	intron_variant	Intron 1 of 18	XP_047301608.1
TPO	XM_047445653.1 link	c.-577+7415A>G	intron_variant	Intron 1 of 18	XP_047301609.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL
TPO	ENST00000497517.6 link	n.180+7415A>G	intron_variant	Intron 1 of 5	1
TPO	ENST00000650224.1 link	n.337+7415A>G	intron_variant	Intron 1 of 3
ENSG00000231482	ENST00000650512.1 link	n.866-14324T>C	intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.0578

AC:

8787

AN:

152064

Hom.:

669

Cov.:

show subpopulations

Gnomad AFR

AF:

0.132

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0522

Gnomad ASJ

AF:

0.00606

Gnomad EAS

AF:

0.304

Gnomad SAS

AF:

0.0305

Gnomad FIN

AF:

0.0229

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00679

Gnomad OTH

AF:

0.0402

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

GnomAD4 genome

AF:

0.0579

AC:

8805

AN:

152182

Hom.:

672

Cov.:

AF XY:

0.0595

AC XY:

4428

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.132

AC:

5477

AN:

41510

American (AMR)

AF:

0.0522

AC:

799

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00606

AC:

AN:

3468

East Asian (EAS)

AF:

0.304

AC:

1565

AN:

5152

South Asian (SAS)

AF:

0.0303

AC:

146

AN:

4816

European-Finnish (FIN)

AF:

0.0229

AC:

243

AN:

10608

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00681

AC:

463

AN:

68014

Other (OTH)

AF:

0.0407

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

364

727

1091

1454

1818

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

276

368

460

<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:

0.0402

Hom.:

227

Bravo

AF:

0.0647

Asia WGS

AF:

0.128

AC:

446

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

7.3

(source)

DANN

Benign

0.28

PhyloP100

1.3

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