ENST00000329066:c.-75A>C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000329066.9(TPO):​c.-75A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TPO ENST00000329066.9 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000329066.9. 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>C		5_prime_UTR	Exon 1 of 17	NP_001193673.1	P07202-1
	TPO	NM_000547.6		c.-80A>C		5_prime_UTR	Exon 1 of 17	NP_000538.3
	TPO	NM_001206745.2		c.-75A>C		5_prime_UTR	Exon 1 of 16	NP_001193674.1	P07202-2

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 10570 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 5344

African (AFR) AF: 0.00 AC: 0 AN: 190

American (AMR) AF: 0.00 AC: 0 AN: 22

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 56

East Asian (EAS) AF: 0.00 AC: 0 AN: 30

South Asian (SAS) AF: 0.00 AC: 0 AN: 242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 24

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 9670

Other (OTH) AF: 0.00 AC: 0 AN: 330

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.5
DANN	Benign	0.66
PhyloP100		-0.81
PromoterAI		0.0030	Neutral

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;