rs1126799

Positions:

• chr2-1516904-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001206744.2(TPO):​c.2540T>C​(p.Val847Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.56 in 1,613,542 control chromosomes in the GnomAD database, including 256,715 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (30292 hom., cov: 33)
  • Exomes 𝑓: 0.55 (226423 hom.)
• Consequence: TPO NM_001206744.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.630

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.9479213E-6).
• BP6: Variant 2-1516904-T-C is Benign according to our data. Variant chr2-1516904-T-C is described in ClinVar as [Benign]. Clinvar id is 256614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-1516904-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.772 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPO	NM_001206744.2	c.2540T>C	p.Val847Ala	missense_variant	15/17	ENST00000329066.9	NP_001193673.1
LOC124905966	XR_007086185.1	n.166+24918A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPO	ENST00000329066.9	c.2540T>C	p.Val847Ala	missense_variant	15/17	1	NM_001206744.2	ENSP00000329869	P1
	ENST00000650512.1	n.547+63297A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.622 AC: 94584 AN: 151998 Hom.: 30241 Cov.: 33

Gnomad AFR AF: 0.778

Gnomad AMI AF: 0.520

Gnomad AMR AF: 0.613

Gnomad ASJ AF: 0.505

Gnomad EAS AF: 0.597

Gnomad SAS AF: 0.656

Gnomad FIN AF: 0.613

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.539

Gnomad OTH AF: 0.586

GnomAD3 exomes AF: 0.587 AC: 147233 AN: 250810 Hom.: 44029 AF XY: 0.583 AC XY: 79187 AN XY: 135728

Gnomad AFR exome AF: 0.783

Gnomad AMR exome AF: 0.621

Gnomad ASJ exome AF: 0.480

Gnomad EAS exome AF: 0.587

Gnomad SAS exome AF: 0.659

Gnomad FIN exome AF: 0.609

Gnomad NFE exome AF: 0.537

Gnomad OTH exome AF: 0.551

GnomAD4 exome AF: 0.554 AC: 808956 AN: 1461426 Hom.: 226423 Cov.: 62 AF XY: 0.555 AC XY: 403796 AN XY: 727020

Gnomad4 AFR exome AF: 0.791

Gnomad4 AMR exome AF: 0.619

Gnomad4 ASJ exome AF: 0.485

Gnomad4 EAS exome AF: 0.623

Gnomad4 SAS exome AF: 0.651

Gnomad4 FIN exome AF: 0.602

Gnomad4 NFE exome AF: 0.533

Gnomad4 OTH exome AF: 0.564

GnomAD4 genome AF: 0.623 AC: 94699 AN: 152116 Hom.: 30292 Cov.: 33 AF XY: 0.624 AC XY: 46406 AN XY: 74370

Gnomad4 AFR AF: 0.779

Gnomad4 AMR AF: 0.613

Gnomad4 ASJ AF: 0.505

Gnomad4 EAS AF: 0.598

Gnomad4 SAS AF: 0.656

Gnomad4 FIN AF: 0.613

Gnomad4 NFE AF: 0.539

Gnomad4 OTH AF: 0.587

Alfa AF: 0.548 Hom.: 45321

Bravo AF: 0.626

TwinsUK AF: 0.519 AC: 1923

ALSPAC AF: 0.526 AC: 2028

ESP6500AA AF: 0.771 AC: 3398

ESP6500EA AF: 0.532 AC: 4578

ExAC AF: 0.589 AC: 71519

Asia WGS AF: 0.655 AC: 2276 AN: 3478

EpiCase AF: 0.527

EpiControl AF: 0.522

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Deficiency of iodide peroxidase Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	4.6
DANN	Benign	0.19
DEOGEN2	Benign	0.26	T;T;.;.;.;.;.
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.0011	N
LIST_S2	Benign	0.28	T;.;T;T;T;T;T
MetaRNN	Benign	0.0000029	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.6	N;N;.;.;.;.;.
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Benign	0.41	T
PROVEAN	Benign	1.7	N;N;N;N;N;N;N
REVEL	Uncertain	0.32
Sift	Benign	1.0	T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;B;.;.
Vest4		0.036
MPC		0.19
ClinPred		0.011	T
GERP RS		4.6
Varity_R		0.033
gMVP		0.59

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: rs1126799; hg19: chr2-1520676; COSMIC: COSV61097695;