chr2-1374288-G-A

Variant names:

• chr2-1374288-G-A
• rs4927602
• ENST00000497517.6:n.66G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000898235.1(TPO):​c.-691G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.593 in 152,086 control chromosomes in the GnomAD database, including 27,974 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 (27973 hom., cov: 33)
  • Exomes 𝑓: 0.33 (1 hom.)
• Consequence: TPO ENST00000898235.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.239
• Publications: 6 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:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.764 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000898235.1. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPO	ENST00000497517.6	TSL:1	n.66G>A		non_coding_transcript_exon	Exon 1 of 6
	TPO	ENST00000898235.1		c.-691G>A		5_prime_UTR	Exon 1 of 21	ENSP00000568294.1
	TPO	ENST00000898236.1		c.-295G>A		5_prime_UTR	Exon 1 of 18	ENSP00000568295.1

Frequencies

GnomAD3 genomes AF: 0.593 AC: 90067 AN: 151958 Hom.: 27912 Cov.: 33

Gnomad AFR AF: 0.771

Gnomad AMI AF: 0.508

Gnomad AMR AF: 0.598

Gnomad ASJ AF: 0.415

Gnomad EAS AF: 0.583

Gnomad SAS AF: 0.519

Gnomad FIN AF: 0.582

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.502

Gnomad OTH AF: 0.574

GnomAD4 exome AF: 0.333 AC: 4 AN: 12 Hom.: 1 Cov.: 0 AF XY: 0.500 AC XY: 4 AN XY: 8

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 1.00 AC: 2 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.250 AC: 2 AN: 8

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.593 AC: 90189 AN: 152074 Hom.: 27973 Cov.: 33 AF XY: 0.593 AC XY: 44064 AN XY: 74340

African (AFR) AF: 0.772 AC: 32035 AN: 41520

American (AMR) AF: 0.599 AC: 9155 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.415 AC: 1438 AN: 3468

East Asian (EAS) AF: 0.582 AC: 3004 AN: 5162

South Asian (SAS) AF: 0.520 AC: 2507 AN: 4822

European-Finnish (FIN) AF: 0.582 AC: 6153 AN: 10564

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.502 AC: 34092 AN: 67934

Other (OTH) AF: 0.576 AC: 1215 AN: 2108

Alfa AF: 0.529 Hom.: 25105

Bravo AF: 0.601

Asia WGS AF: 0.575 AC: 2003 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.4
DANN	Benign	0.49
PhyloP100		-0.24

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4927602; hg19: chr2-1378060;