chr2-1541338-G-A

Variant names:

• chr2-1541338-G-A
• rs4927632
• NM_001206744.2:c.2748+615G>A

Variant summary

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

The NM_001206744.2(TPO):​c.2748+615G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.603 in 294,056 control chromosomes in the GnomAD database, including 54,576 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 (26737 hom., cov: 31)
  • Exomes 𝑓: 0.62 (27839 hom.)
• Consequence: TPO NM_001206744.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.575
• 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:):

ENSG00000228613 (HGNC:58132):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.628 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPO	NM_001206744.2	c.2748+615G>A		intron_variant	Intron 16 of 16	ENST00000329066.9	NP_001193673.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPO	ENST00000329066.9	c.2748+615G>A		intron_variant	Intron 16 of 16	1	NM_001206744.2	ENSP00000329869.4

Frequencies

GnomAD3 genomes AF: 0.591 AC: 89559 AN: 151500 Hom.: 26720 Cov.: 31

Gnomad AFR AF: 0.516

Gnomad AMI AF: 0.620

Gnomad AMR AF: 0.584

Gnomad ASJ AF: 0.675

Gnomad EAS AF: 0.517

Gnomad SAS AF: 0.540

Gnomad FIN AF: 0.653

Gnomad MID AF: 0.596

Gnomad NFE AF: 0.633

Gnomad OTH AF: 0.600

GnomAD4 exome AF: 0.616 AC: 87702 AN: 142440 Hom.: 27839 Cov.: 5 AF XY: 0.615 AC XY: 42602 AN XY: 69240

African (AFR) AF: 0.481 AC: 1261 AN: 2622

American (AMR) AF: 0.615 AC: 1802 AN: 2932

Ashkenazi Jewish (ASJ) AF: 0.671 AC: 652 AN: 972

East Asian (EAS) AF: 0.491 AC: 807 AN: 1644

South Asian (SAS) AF: 0.518 AC: 2378 AN: 4590

European-Finnish (FIN) AF: 0.598 AC: 153 AN: 256

Middle Eastern (MID) AF: 0.620 AC: 160 AN: 258

European-Non Finnish (NFE) AF: 0.624 AC: 77548 AN: 124298

Other (OTH) AF: 0.604 AC: 2941 AN: 4868

GnomAD4 genome AF: 0.591 AC: 89613 AN: 151616 Hom.: 26737 Cov.: 31 AF XY: 0.590 AC XY: 43705 AN XY: 74068

African (AFR) AF: 0.516 AC: 21285 AN: 41260

American (AMR) AF: 0.585 AC: 8912 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.675 AC: 2342 AN: 3468

East Asian (EAS) AF: 0.517 AC: 2658 AN: 5142

South Asian (SAS) AF: 0.540 AC: 2596 AN: 4806

European-Finnish (FIN) AF: 0.653 AC: 6836 AN: 10464

Middle Eastern (MID) AF: 0.599 AC: 175 AN: 292

European-Non Finnish (NFE) AF: 0.633 AC: 42990 AN: 67928

Other (OTH) AF: 0.598 AC: 1256 AN: 2102

Alfa AF: 0.626 Hom.: 15101

Bravo AF: 0.585

Asia WGS AF: 0.510 AC: 1777 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	0.55
DANN	Benign	0.33
PhyloP100		-0.57
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: rs4927632; hg19: chr2-1545110;