chr2-1374288-G-A

Position:

• chr2-1374288-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000497517.6(TPO):​n.66G>A variant causes a non coding transcript exon 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 ENST00000497517.6 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.239

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 -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPO	XM_024453089.2	c.-595G>A		5_prime_UTR_variant	1/18
TPO	XM_047445652.1	c.-1506G>A		5_prime_UTR_variant	1/19
TPO	XM_047445653.1	c.-691G>A		5_prime_UTR_variant	1/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPO	ENST00000497517.6	n.66G>A		non_coding_transcript_exon_variant	1/6	1
	ENST00000650512.1	n.866-6795C>T		intron_variant, non_coding_transcript_variant
TPO	ENST00000650224.1	n.223G>A		non_coding_transcript_exon_variant	1/4

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

Gnomad4 EAS exome AF: 1.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.250

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

Gnomad4 AFR AF: 0.772

Gnomad4 AMR AF: 0.599

Gnomad4 ASJ AF: 0.415

Gnomad4 EAS AF: 0.582

Gnomad4 SAS AF: 0.520

Gnomad4 FIN AF: 0.582

Gnomad4 NFE AF: 0.502

Gnomad4 OTH AF: 0.576

Alfa AF: 0.517 Hom.: 16324

Bravo AF: 0.601

Asia WGS AF: 0.575 AC: 2003 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs4927602; hg19: chr2-1378060;