2-1487063-C-G

Variant names:

• chr2-1487063-C-G
• rs2361748
• NM_001206744.2:c.1598-758C>G

Variant summary

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

The NM_001206744.2(TPO):​c.1598-758C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 152,188 control chromosomes in the GnomAD database, including 2,233 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 0.15 (2233 hom., cov: 33)
• Consequence: TPO NM_001206744.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.948
• Publications: 1 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: Labcorp Genetics (formerly Invitae)
• familial thyroid dyshormonogenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000231482 (HGNC:):

ENSG00000228613 (HGNC:58132):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPO	NM_001206744.2	c.1598-758C>G		intron_variant	Intron 9 of 16	ENST00000329066.9	NP_001193673.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPO	ENST00000329066.9	c.1598-758C>G		intron_variant	Intron 9 of 16	1	NM_001206744.2	ENSP00000329869.4

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22433 AN: 152070 Hom.: 2221 Cov.: 33

Gnomad AFR AF: 0.270

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.252

Gnomad SAS AF: 0.152

Gnomad FIN AF: 0.0489

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.0916

Gnomad OTH AF: 0.153

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

GnomAD4 genome AF: 0.148 AC: 22472 AN: 152188 Hom.: 2233 Cov.: 33 AF XY: 0.145 AC XY: 10772 AN XY: 74416

African (AFR) AF: 0.271 AC: 11243 AN: 41510

American (AMR) AF: 0.103 AC: 1570 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 451 AN: 3472

East Asian (EAS) AF: 0.252 AC: 1298 AN: 5150

South Asian (SAS) AF: 0.152 AC: 731 AN: 4818

European-Finnish (FIN) AF: 0.0489 AC: 519 AN: 10618

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.0916 AC: 6228 AN: 68012

Other (OTH) AF: 0.156 AC: 330 AN: 2110

Alfa AF: 0.0222 Hom.: 17

Bravo AF: 0.158

Asia WGS AF: 0.214 AC: 744 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	0.47
DANN	Benign	0.67
PhyloP100		-0.95
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: rs2361748; hg19: chr2-1490835;