rs2175977

chr2-1477459-G-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.1193G>C(p.Ser398Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.622 in 1,525,816 control chromosomes in the GnomAD database, including 297,044 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33425 hom., cov: 35)
  • Exomes 𝑓: 0.62 (263619 hom.)
• Consequence: TPO NM_001206744.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.05

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=1.0097892E-6).
• BP6: Variant 2-1477459-G-C is Benign according to our data. Variant chr2-1477459-G-C is described in ClinVar as [Benign]. Clinvar id is 256606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-1477459-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.781 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPO	NM_001206744.2	c.1193G>C	p.Ser398Thr	missense_variant	8/17	ENST00000329066.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPO	ENST00000329066.9	c.1193G>C	p.Ser398Thr	missense_variant	8/17	1	NM_001206744.2	P1
	ENST00000650512.1	n.548-58998C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.657 AC: 99771 AN: 151964 Hom.: 33392 Cov.: 35

Gnomad AFR AF: 0.788

Gnomad AMI AF: 0.547

Gnomad AMR AF: 0.610

Gnomad ASJ AF: 0.551

Gnomad EAS AF: 0.772

Gnomad SAS AF: 0.647

Gnomad FIN AF: 0.549

Gnomad MID AF: 0.678

Gnomad NFE AF: 0.603

Gnomad OTH AF: 0.637

GnomAD3 exomes AF: 0.639 AC: 77787 AN: 121698 Hom.: 25209 AF XY: 0.636 AC XY: 42713 AN XY: 67148

Gnomad AFR exome AF: 0.826

Gnomad AMR exome AF: 0.650

Gnomad ASJ exome AF: 0.573

Gnomad EAS exome AF: 0.790

Gnomad SAS exome AF: 0.636

Gnomad FIN exome AF: 0.549

Gnomad NFE exome AF: 0.614

Gnomad OTH exome AF: 0.611

GnomAD4 exome AF: 0.618 AC: 848771 AN: 1373744 Hom.: 263619 Cov.: 114 AF XY: 0.618 AC XY: 418908 AN XY: 677872

Gnomad4 AFR exome AF: 0.797

Gnomad4 AMR exome AF: 0.644

Gnomad4 ASJ exome AF: 0.566

Gnomad4 EAS exome AF: 0.755

Gnomad4 SAS exome AF: 0.638

Gnomad4 FIN exome AF: 0.558

Gnomad4 NFE exome AF: 0.609

Gnomad4 OTH exome AF: 0.622

GnomAD4 genome AF: 0.657 AC: 99851 AN: 152072 Hom.: 33425 Cov.: 35 AF XY: 0.655 AC XY: 48679 AN XY: 74336

Gnomad4 AFR AF: 0.788

Gnomad4 AMR AF: 0.610

Gnomad4 ASJ AF: 0.551

Gnomad4 EAS AF: 0.772

Gnomad4 SAS AF: 0.648

Gnomad4 FIN AF: 0.549

Gnomad4 NFE AF: 0.603

Gnomad4 OTH AF: 0.636

Alfa AF: 0.621 Hom.: 6058

Bravo AF: 0.669

TwinsUK AF: 0.607 AC: 2250

ALSPAC AF: 0.608 AC: 2344

ESP6500AA AF: 0.864 AC: 2498

ESP6500EA AF: 0.740 AC: 4199

ExAC AF: 0.469 AC: 22060

Asia WGS AF: 0.679 AC: 2355 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Deficiency of iodide peroxidase Benign:2

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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D;D;.;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.53	T;.;T;T;T
MetaRNN	Benign	0.0000010	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;M;M;M;.
MutationTaster	Benign	0.83	P;P;P;P;P;P;P
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.1	N;N;N;N;N
REVEL	Benign	0.26
Sift	Benign	0.15	T;T;T;T;T
Sift4G	Benign	0.14	T;T;T;T;T
Polyphen		1.0	D;D;D;D;.
Vest4		0.036
MPC		1.8
ClinPred		0.034	T
GERP RS		4.1
Varity_R		0.28
gMVP		0.64

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: rs2175977; hg19: chr2-1481231; COSMIC: COSV61103813;