rs10189329

Variant names:

• chr2-1494059-G-A
• rs10189329
• NM_001206744.2:c.2006+20G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000547.6(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_000547.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.97
• 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: 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 -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 VariationId is 256609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000547.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPO	NM_001206744.2	MANE Select	c.2006+20G>A		intron	N/A	NP_001193673.1
	TPO	NM_000547.6		c.2006+20G>A		intron	N/A	NP_000538.3
	TPO	NM_175721.3		c.2006+20G>A		intron	N/A	NP_783652.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPO	ENST00000329066.9	TSL:1 MANE Select	c.2006+20G>A		intron	N/A	ENSP00000329869.4
	TPO	ENST00000345913.8	TSL:1	c.2006+20G>A		intron	N/A	ENSP00000318820.7
	TPO	ENST00000382201.7	TSL:1	c.1835+20G>A		intron	N/A	ENSP00000371636.3

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

GnomAD2 exomes AF: 0.0604 AC: 15064 AN: 249490 AF XY: 0.0596

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 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

African (AFR) AF: 0.209 AC: 6982 AN: 33402

American (AMR) AF: 0.0299 AC: 1335 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0910 AC: 2378 AN: 26126

East Asian (EAS) AF: 0.106 AC: 4192 AN: 39686

South Asian (SAS) AF: 0.0881 AC: 7595 AN: 86196

European-Finnish (FIN) AF: 0.0301 AC: 1601 AN: 53272

Middle Eastern (MID) AF: 0.0903 AC: 519 AN: 5750

European-Non Finnish (NFE) AF: 0.0364 AC: 40357 AN: 1109090

Other (OTH) AF: 0.0605 AC: 3650 AN: 60296

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

African (AFR) AF: 0.195 AC: 8081 AN: 41480

American (AMR) AF: 0.0433 AC: 663 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 372 AN: 3470

East Asian (EAS) AF: 0.104 AC: 539 AN: 5168

South Asian (SAS) AF: 0.103 AC: 498 AN: 4822

European-Finnish (FIN) AF: 0.0294 AC: 312 AN: 10618

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0374 AC: 2545 AN: 68026

Other (OTH) AF: 0.0946 AC: 200 AN: 2114

Alfa AF: 0.0558 Hom.: 520

Bravo AF: 0.0933

Asia WGS AF: 0.137 AC: 477 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.010
DANN	Benign	0.38
PhyloP100		-2.0
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: rs10189329; hg19: chr2-1497831; COSMIC: COSV61097682;