rs10189329

chr2-1494059-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001206744.2(TPO):c.2006+20G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0508 in 1,610,738 control chromosomes in the GnomAD database, including 3,486 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.087 (982 hom., cov: 33)
  • Exomes 𝑓: 0.047 (2504 hom.)
• Consequence: TPO NM_001206744.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.97

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.06).
• BP6: Variant 2-1494059-G-A is Benign according to our data. Variant chr2-1494059-G-A is described in ClinVar as [Benign]. Clinvar id is 256609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-1494059-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPO	NM_001206744.2	c.2006+20G>A		intron_variant		ENST00000329066.9
LOC124905966	XR_007086185.1	n.167-7868C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPO	ENST00000329066.9	c.2006+20G>A		intron_variant		1	NM_001206744.2	P1
	ENST00000650512.1	n.548-75598C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0871 AC: 13250 AN: 152082 Hom.: 975 Cov.: 33

Gnomad AFR AF: 0.195

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0435

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.104

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.0294

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0374

Gnomad OTH AF: 0.0908

GnomAD3 exomes AF: 0.0604 AC: 15064 AN: 249490 Hom.: 760 AF XY: 0.0596 AC XY: 8048 AN XY: 135092

Gnomad AFR exome AF: 0.203

Gnomad AMR exome AF: 0.0268

Gnomad ASJ exome AF: 0.0916

Gnomad EAS exome AF: 0.103

Gnomad SAS exome AF: 0.0912

Gnomad FIN exome AF: 0.0299

Gnomad NFE exome AF: 0.0382

Gnomad OTH exome AF: 0.0529

GnomAD4 exome AF: 0.0470 AC: 68609 AN: 1458538 Hom.: 2504 Cov.: 32 AF XY: 0.0480 AC XY: 34827 AN XY: 725780

Gnomad4 AFR exome AF: 0.209

Gnomad4 AMR exome AF: 0.0299

Gnomad4 ASJ exome AF: 0.0910

Gnomad4 EAS exome AF: 0.106

Gnomad4 SAS exome AF: 0.0881

Gnomad4 FIN exome AF: 0.0301

Gnomad4 NFE exome AF: 0.0364

Gnomad4 OTH exome AF: 0.0605

GnomAD4 genome AF: 0.0872 AC: 13277 AN: 152200 Hom.: 982 Cov.: 33 AF XY: 0.0857 AC XY: 6376 AN XY: 74414

Gnomad4 AFR AF: 0.195

Gnomad4 AMR AF: 0.0433

Gnomad4 ASJ AF: 0.107

Gnomad4 EAS AF: 0.104

Gnomad4 SAS AF: 0.103

Gnomad4 FIN AF: 0.0294

Gnomad4 NFE AF: 0.0374

Gnomad4 OTH AF: 0.0946

Alfa AF: 0.0508 Hom.: 319

Bravo AF: 0.0933

Asia WGS AF: 0.137 AC: 477 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 20, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
Cadd	Benign	0.010
Dann	Benign	0.38

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: rs10189329; hg19: chr2-1497831; COSMIC: COSV61097682;