Genetic Variant TPO:n.66G>A (chr2-1374288-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The XM_024453089.2(TPO):c.-595G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.593 in 152,086 control chromosomes in the GnomAD database, including 27,974 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 0.59 ( 27973 hom., cov: 33)

Exomes 𝑓: 0.33 ( 1 hom. )

Consequence

TPO
XM_024453089.2 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.239

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 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=-1.0).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.764 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein
TPO	XM_024453089.2 link	c.-595G>A	5_prime_UTR_variant	Exon 1 of 18	XP_024308857.1
TPO	XM_047445652.1 link	c.-1506G>A	5_prime_UTR_variant	Exon 1 of 19	XP_047301608.1
TPO	XM_047445653.1 link	c.-691G>A	5_prime_UTR_variant	Exon 1 of 19	XP_047301609.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL
TPO	ENST00000497517.6 link	n.66G>A	non_coding_transcript_exon_variant	Exon 1 of 6	1
TPO	ENST00000650224.1 link	n.223G>A	non_coding_transcript_exon_variant	Exon 1 of 4
ENSG00000231482	ENST00000650512.1 link	n.866-6795C>T	intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.593

AC:

90067

AN:

151958

Hom.:

27912

Cov.:

show subpopulations

Gnomad AFR

AF:

0.771

Gnomad AMI

AF:

0.508

Gnomad AMR

AF:

0.598

Gnomad ASJ

AF:

0.415

Gnomad EAS

AF:

0.583

Gnomad SAS

AF:

0.519

Gnomad FIN

AF:

0.582

Gnomad MID

AF:

0.430

Gnomad NFE

AF:

0.502

Gnomad OTH

AF:

0.574

GnomAD4 exome

AF:

0.333

AC:

AN:

Hom.:

Cov.:

AF XY:

0.500

AC XY:

AN XY:

show subpopulations

Gnomad4 AFR exome

AC:

AN:

Gnomad4 AMR exome

AC:

AN:

Gnomad4 ASJ exome

AC:

AN:

Gnomad4 EAS exome

AF:

1.00

AC:

AN:

Gnomad4 SAS exome

AC:

AN:

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

Gnomad4 NFE exome

AF:

0.250

AC:

AN:

Gnomad4 Remaining exome

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.593

AC:

90189

AN:

152074

Hom.:

27973

Cov.:

AF XY:

0.593

AC XY:

44064

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.772

AC:

0.771556

AN:

0.771556

Gnomad4 AMR

AF:

0.599

AC:

0.598757

AN:

0.598757

Gnomad4 ASJ

AF:

0.415

AC:

0.414648

AN:

0.414648

Gnomad4 EAS

AF:

0.582

AC:

0.581945

AN:

0.581945

Gnomad4 SAS

AF:

0.520

AC:

0.519909

AN:

0.519909

Gnomad4 FIN

AF:

0.582

AC:

0.58245

AN:

0.58245

Gnomad4 NFE

AF:

0.502

AC:

0.50184

AN:

0.50184

Gnomad4 OTH

AF:

0.576

AC:

0.576376

AN:

0.576376

Heterozygous variant carriers

1806

3612

5418

7224

9030

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

736

1472

2208

2944

3680

<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:

0.529

Hom.:

25105

Bravo

AF:

0.601

Asia WGS

AF:

0.575

AC:

2003

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

2.4

DANN

Benign

0.49

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over