2-1515292-C-T

Variant names:

• chr2-1515292-C-T
• rs17732233
• NM_001206744.2:c.2519-1591C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001206744.2(TPO):​c.2519-1591C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.283 in 152,080 control chromosomes in the GnomAD database, including 6,396 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 0.28 (6396 hom., cov: 33)
• Consequence: TPO NM_001206744.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.373
• Publications: 5 publications found

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: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• familial thyroid dyshormonogenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000231482 (HGNC:):

LALTOP (HGNC:58132):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.323 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001206744.2. 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
	TPO	NM_001206744.2	MANE Select	c.2519-1591C>T		intron	N/A	NP_001193673.1	P07202-1
	TPO	NM_000547.6		c.2519-1591C>T		intron	N/A	NP_000538.3
	TPO	NM_175721.3		c.2387-1591C>T		intron	N/A	NP_783652.1	P07202-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPO	ENST00000329066.9	TSL:1 MANE Select	c.2519-1591C>T		intron	N/A	ENSP00000329869.4	P07202-1
	TPO	ENST00000345913.8	TSL:1	c.2519-1591C>T		intron	N/A	ENSP00000318820.7	P07202-1
	TPO	ENST00000382201.7	TSL:1	c.2348-1591C>T		intron	N/A	ENSP00000371636.3	P07202-2

Frequencies

GnomAD3 genomes AF: 0.283 AC: 43056 AN: 151962 Hom.: 6396 Cov.: 33

Gnomad AFR AF: 0.179

Gnomad AMI AF: 0.376

Gnomad AMR AF: 0.330

Gnomad ASJ AF: 0.321

Gnomad EAS AF: 0.243

Gnomad SAS AF: 0.326

Gnomad FIN AF: 0.371

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.319

Gnomad OTH AF: 0.290

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

GnomAD4 genome AF: 0.283 AC: 43063 AN: 152080 Hom.: 6396 Cov.: 33 AF XY: 0.286 AC XY: 21243 AN XY: 74328

African (AFR) AF: 0.178 AC: 7404 AN: 41500

American (AMR) AF: 0.330 AC: 5050 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 1114 AN: 3472

East Asian (EAS) AF: 0.243 AC: 1251 AN: 5148

South Asian (SAS) AF: 0.326 AC: 1566 AN: 4806

European-Finnish (FIN) AF: 0.371 AC: 3927 AN: 10572

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.319 AC: 21714 AN: 67986

Other (OTH) AF: 0.288 AC: 609 AN: 2114

Alfa AF: 0.306 Hom.: 11757

Bravo AF: 0.273

Asia WGS AF: 0.296 AC: 1027 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.9
DANN	Benign	0.29
PhyloP100		-0.37
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs17732233; hg19: chr2-1519064;