rs2071403

Variant names:

• chr2-1413472-A-G
• rs2071403
• NM_001206744.2:c.-75A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-1413472-A-G
• chr2-1413472-A-C
• chr2-1413472-A-T

Variant summary

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

The NM_001206744.2(TPO):​c.-75A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.565 in 162,578 control chromosomes in the GnomAD database, including 26,357 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (24986 hom., cov: 33)
  • Exomes 𝑓: 0.51 (1371 hom.)
• Consequence: TPO NM_001206744.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.810
• Publications: 22 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:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 2-1413472-A-G is Benign according to our data. Variant chr2-1413472-A-G is described in ClinVar as Benign. ClinVar VariationId is 331215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.654 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.-75A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	NP_001193673.1	P07202-1
	TPO	NM_001206744.2	MANE Select	c.-75A>G		5_prime_UTR	Exon 1 of 17	NP_001193673.1	P07202-1
	TPO	NM_000547.6		c.-80A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	NP_000538.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPO	ENST00000329066.9	TSL:1 MANE Select	c.-75A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	ENSP00000329869.4	P07202-1
	TPO	ENST00000345913.8	TSL:1	c.-80A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	ENSP00000318820.7	P07202-1
	TPO	ENST00000539820.5	TSL:1	c.-80A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000444840.1	E9PFM6

Frequencies

GnomAD3 genomes AF: 0.569 AC: 86452 AN: 151944 Hom.: 24955 Cov.: 33

Gnomad AFR AF: 0.636

Gnomad AMI AF: 0.378

Gnomad AMR AF: 0.664

Gnomad ASJ AF: 0.516

Gnomad EAS AF: 0.653

Gnomad SAS AF: 0.650

Gnomad FIN AF: 0.563

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.502

Gnomad OTH AF: 0.550

GnomAD4 exome AF: 0.510 AC: 5362 AN: 10516 Hom.: 1371 Cov.: 0 AF XY: 0.508 AC XY: 2698 AN XY: 5316

African (AFR) AF: 0.663 AC: 126 AN: 190

American (AMR) AF: 0.545 AC: 12 AN: 22

Ashkenazi Jewish (ASJ) AF: 0.589 AC: 33 AN: 56

East Asian (EAS) AF: 0.600 AC: 18 AN: 30

South Asian (SAS) AF: 0.700 AC: 168 AN: 240

European-Finnish (FIN) AF: 0.500 AC: 3 AN: 6

Middle Eastern (MID) AF: 0.500 AC: 12 AN: 24

European-Non Finnish (NFE) AF: 0.502 AC: 4837 AN: 9626

Other (OTH) AF: 0.475 AC: 153 AN: 322

GnomAD4 genome AF: 0.569 AC: 86545 AN: 152062 Hom.: 24986 Cov.: 33 AF XY: 0.574 AC XY: 42672 AN XY: 74320

African (AFR) AF: 0.636 AC: 26383 AN: 41470

American (AMR) AF: 0.665 AC: 10163 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.516 AC: 1791 AN: 3472

East Asian (EAS) AF: 0.653 AC: 3371 AN: 5160

South Asian (SAS) AF: 0.649 AC: 3127 AN: 4818

European-Finnish (FIN) AF: 0.563 AC: 5944 AN: 10556

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.502 AC: 34117 AN: 67984

Other (OTH) AF: 0.551 AC: 1163 AN: 2112

Alfa AF: 0.526 Hom.: 57375

Bravo AF: 0.577

Asia WGS AF: 0.649 AC: 2253 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Deficiency of iodide peroxidase (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.8
DANN	Benign	0.64
PhyloP100		-0.81
PromoterAI		0.0016	Neutral
Mutation Taster		=300/0	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: rs2071403; hg19: chr2-1417244; COSMIC: COSV61096929; COSMIC: COSV61096929;