rs4927632

Positions:

• chr2-1541338-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001206744.2(TPO):​c.2748+615G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.603 in 294,056 control chromosomes in the GnomAD database, including 54,576 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 (26737 hom., cov: 31)
  • Exomes 𝑓: 0.62 (27839 hom.)
• Consequence: TPO NM_001206744.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.575

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.628 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPO	NM_001206744.2	c.2748+615G>A		intron_variant		ENST00000329066.9	NP_001193673.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPO	ENST00000329066.9	c.2748+615G>A		intron_variant		1	NM_001206744.2	ENSP00000329869.4

Frequencies

GnomAD3 genomes AF: 0.591 AC: 89559 AN: 151500 Hom.: 26720 Cov.: 31

Gnomad AFR AF: 0.516

Gnomad AMI AF: 0.620

Gnomad AMR AF: 0.584

Gnomad ASJ AF: 0.675

Gnomad EAS AF: 0.517

Gnomad SAS AF: 0.540

Gnomad FIN AF: 0.653

Gnomad MID AF: 0.596

Gnomad NFE AF: 0.633

Gnomad OTH AF: 0.600

GnomAD4 exome AF: 0.616 AC: 87702 AN: 142440 Hom.: 27839 Cov.: 5 AF XY: 0.615 AC XY: 42602 AN XY: 69240

Gnomad4 AFR exome AF: 0.481

Gnomad4 AMR exome AF: 0.615

Gnomad4 ASJ exome AF: 0.671

Gnomad4 EAS exome AF: 0.491

Gnomad4 SAS exome AF: 0.518

Gnomad4 FIN exome AF: 0.598

Gnomad4 NFE exome AF: 0.624

Gnomad4 OTH exome AF: 0.604

GnomAD4 genome AF: 0.591 AC: 89613 AN: 151616 Hom.: 26737 Cov.: 31 AF XY: 0.590 AC XY: 43705 AN XY: 74068

Gnomad4 AFR AF: 0.516

Gnomad4 AMR AF: 0.585

Gnomad4 ASJ AF: 0.675

Gnomad4 EAS AF: 0.517

Gnomad4 SAS AF: 0.540

Gnomad4 FIN AF: 0.653

Gnomad4 NFE AF: 0.633

Gnomad4 OTH AF: 0.598

Alfa AF: 0.625 Hom.: 13549

Bravo AF: 0.585

Asia WGS AF: 0.510 AC: 1777 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	0.55
DANN	Benign	0.33

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

Publications

LitVar

Other links and lift over

dbSNP: rs4927632; hg19: chr2-1545110;