rs9678281

Variant names:

• chr2-1414420-C-G
• rs9678281
• NM_001206744.2:c.12C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-1414420-C-G
• chr2-1414420-C-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001206744.2(TPO):​c.12C>G​(p.Leu4Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.372 in 1,611,858 control chromosomes in the GnomAD database, including 113,519 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L4L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.36 (10159 hom., cov: 32)
  • Exomes 𝑓: 0.37 (103360 hom.)
• Consequence: TPO NM_001206744.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.72
• Publications: 19 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 2-1414420-C-G is Benign according to our data. Variant chr2-1414420-C-G is described in ClinVar as Benign. ClinVar VariationId is 256607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.72 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.408 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.12C>G	p.Leu4Leu	synonymous	Exon 2 of 17	NP_001193673.1	P07202-1
	TPO	NM_000547.6		c.12C>G	p.Leu4Leu	synonymous	Exon 2 of 17	NP_000538.3
	TPO	NM_175721.3		c.12C>G	p.Leu4Leu	synonymous	Exon 1 of 15	NP_783652.1	P07202-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPO	ENST00000329066.9	TSL:1 MANE Select	c.12C>G	p.Leu4Leu	synonymous	Exon 2 of 17	ENSP00000329869.4	P07202-1
	TPO	ENST00000345913.8	TSL:1	c.12C>G	p.Leu4Leu	synonymous	Exon 2 of 17	ENSP00000318820.7	P07202-1
	TPO	ENST00000382201.7	TSL:1	c.12C>G	p.Leu4Leu	synonymous	Exon 2 of 16	ENSP00000371636.3	P07202-2

Frequencies

GnomAD3 genomes AF: 0.358 AC: 54395 AN: 151876 Hom.: 10154 Cov.: 32

Gnomad AFR AF: 0.292

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.416

Gnomad ASJ AF: 0.361

Gnomad EAS AF: 0.208

Gnomad SAS AF: 0.336

Gnomad FIN AF: 0.414

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.389

Gnomad OTH AF: 0.353

GnomAD2 exomes AF: 0.365 AC: 91287 AN: 249830 AF XY: 0.363

Gnomad AFR exome AF: 0.292

Gnomad AMR exome AF: 0.411

Gnomad ASJ exome AF: 0.339

Gnomad EAS exome AF: 0.206

Gnomad FIN exome AF: 0.415

Gnomad NFE exome AF: 0.387

Gnomad OTH exome AF: 0.377

GnomAD4 exome AF: 0.374 AC: 545769 AN: 1459864 Hom.: 103360 Cov.: 38 AF XY: 0.373 AC XY: 270594 AN XY: 726262

African (AFR) AF: 0.286 AC: 9574 AN: 33452

American (AMR) AF: 0.411 AC: 18331 AN: 44624

Ashkenazi Jewish (ASJ) AF: 0.339 AC: 8855 AN: 26110

East Asian (EAS) AF: 0.203 AC: 8040 AN: 39686

South Asian (SAS) AF: 0.342 AC: 29466 AN: 86070

European-Finnish (FIN) AF: 0.413 AC: 22036 AN: 53332

Middle Eastern (MID) AF: 0.355 AC: 2047 AN: 5764

European-Non Finnish (NFE) AF: 0.383 AC: 425599 AN: 1110500

Other (OTH) AF: 0.362 AC: 21821 AN: 60326

GnomAD4 genome AF: 0.358 AC: 54414 AN: 151994 Hom.: 10159 Cov.: 32 AF XY: 0.357 AC XY: 26531 AN XY: 74256

African (AFR) AF: 0.291 AC: 12073 AN: 41448

American (AMR) AF: 0.417 AC: 6368 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.361 AC: 1252 AN: 3472

East Asian (EAS) AF: 0.207 AC: 1068 AN: 5156

South Asian (SAS) AF: 0.335 AC: 1614 AN: 4818

European-Finnish (FIN) AF: 0.414 AC: 4361 AN: 10540

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.389 AC: 26468 AN: 67972

Other (OTH) AF: 0.352 AC: 741 AN: 2108

Alfa AF: 0.301 Hom.: 1255

Bravo AF: 0.353

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Deficiency of iodide peroxidase (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.012
DANN	Benign	0.31
PhyloP100		-3.7
PromoterAI		0.025	Neutral
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: rs9678281; hg19: chr2-1418192; COSMIC: COSV61100536;