chr2-1414420-C-G

Position:

• chr2-1414420-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001206744.2(TPO):​c.12C>G​(p.Leu4=) 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:7
• Conservation: PhyloP100: -3.72

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 -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 id is 256607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-1414420-C-G is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPO	NM_001206744.2	c.12C>G	p.Leu4=	synonymous_variant	2/17	ENST00000329066.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPO	ENST00000329066.9	c.12C>G	p.Leu4=	synonymous_variant	2/17	1	NM_001206744.2	P1
	ENST00000650512.1	n.646+3943G>C		intron_variant, non_coding_transcript_variant

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

GnomAD3 exomes AF: 0.365 AC: 91287 AN: 249830 Hom.: 17087 AF XY: 0.363 AC XY: 49076 AN XY: 135082

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 SAS exome AF: 0.341

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

Gnomad4 AFR exome AF: 0.286

Gnomad4 AMR exome AF: 0.411

Gnomad4 ASJ exome AF: 0.339

Gnomad4 EAS exome AF: 0.203

Gnomad4 SAS exome AF: 0.342

Gnomad4 FIN exome AF: 0.413

Gnomad4 NFE exome AF: 0.383

Gnomad4 OTH exome AF: 0.362

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

Gnomad4 AFR AF: 0.291

Gnomad4 AMR AF: 0.417

Gnomad4 ASJ AF: 0.361

Gnomad4 EAS AF: 0.207

Gnomad4 SAS AF: 0.335

Gnomad4 FIN AF: 0.414

Gnomad4 NFE AF: 0.389

Gnomad4 OTH AF: 0.352

Alfa AF: 0.301 Hom.: 1255

Bravo AF: 0.353

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Deficiency of iodide peroxidase Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.012
DANN	Benign	0.31

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

Publications

LitVar

Other links and lift over

dbSNP: rs9678281; hg19: chr2-1418192; COSMIC: COSV61100536;