dbSNP rs11694732: TPO:n.180+30176G>C (chr2-1404578-G-C) – 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+30176G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.39 in 152,006 control chromosomes in the GnomAD database, including 11,761 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 0.39 ( 11761 hom., cov: 32)

Consequence

TPO
ENST00000497517.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.760

Publications

6 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=-0.84).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.477 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein
TPO	XM_024453089.2 link	c.-480-2415G>C	intron_variant	Intron 1 of 17	XP_024308857.1
TPO	XM_047445652.1 link	c.-481+480G>C	intron_variant	Intron 2 of 18	XP_047301608.1
TPO	XM_047445653.1 link	c.-481+480G>C	intron_variant	Intron 2 of 18	XP_047301609.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL
TPO	ENST00000497517.6 link	n.180+30176G>C	intron_variant	Intron 1 of 5	1
TPO	ENST00000650224.1 link	n.433+480G>C	intron_variant	Intron 2 of 3
ENSG00000231482	ENST00000650512.1 link	n.865+4951C>G	intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.390

AC:

59209

AN:

151888

Hom.:

11749

Cov.:

show subpopulations

Gnomad AFR

AF:

0.307

Gnomad AMI

AF:

0.349

Gnomad AMR

AF:

0.485

Gnomad ASJ

AF:

0.473

Gnomad EAS

AF:

0.297

Gnomad SAS

AF:

0.456

Gnomad FIN

AF:

0.431

Gnomad MID

AF:

0.361

Gnomad NFE

AF:

0.411

Gnomad OTH

AF:

0.386

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

GnomAD4 genome

AF:

0.390

AC:

59255

AN:

152006

Hom.:

11761

Cov.:

AF XY:

0.390

AC XY:

28997

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.307

AC:

12734

AN:

41458

American (AMR)

AF:

0.486

AC:

7423

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.473

AC:

1639

AN:

3468

East Asian (EAS)

AF:

0.296

AC:

1523

AN:

5150

South Asian (SAS)

AF:

0.454

AC:

2188

AN:

4820

European-Finnish (FIN)

AF:

0.431

AC:

4549

AN:

10566

Middle Eastern (MID)

AF:

0.361

AC:

106

AN:

294

European-Non Finnish (NFE)

AF:

0.411

AC:

27960

AN:

67954

Other (OTH)

AF:

0.386

AC:

815

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

1753

3506

5258

7011

8764

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

570

1140

1710

2280

2850

<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:

0.288

Hom.:

762

Bravo

AF:

0.388

Asia WGS

AF:

0.411

AC:

1425

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

2.3

(source)

DANN

Benign

0.77

PhyloP100

0.76

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