rs1057518950

Variant names:

• chr2-1484815-C-T
• rs1057518950
• NM_001206744.2:c.1558C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_001206744.2(TPO):​c.1558C>T​(p.His520Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TPO NM_001206744.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.42
• Publications: 1 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:):

LALTOP (HGNC:58132):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.767
• PP5: Variant 2-1484815-C-T is Pathogenic according to our data. Variant chr2-1484815-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 374178.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1558C>T	p.His520Tyr	missense	Exon 9 of 17	NP_001193673.1
	TPO	NM_000547.6		c.1558C>T	p.His520Tyr	missense	Exon 9 of 17	NP_000538.3
	TPO	NM_175721.3		c.1558C>T	p.His520Tyr	missense	Exon 8 of 15	NP_783652.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPO	ENST00000329066.9	TSL:1 MANE Select	c.1558C>T	p.His520Tyr	missense	Exon 9 of 17	ENSP00000329869.4
	TPO	ENST00000345913.8	TSL:1	c.1558C>T	p.His520Tyr	missense	Exon 9 of 17	ENSP00000318820.7
	TPO	ENST00000382201.7	TSL:1	c.1558C>T	p.His520Tyr	missense	Exon 9 of 16	ENSP00000371636.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461708 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727154

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53242

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Congenital hypothyroidism;C0036857:severe intellectual disability;C0241442:Protruding tongue;C0349588:Short stature;C0454644:Delayed speech and language development;C0557874:Global developmental delay;C1837658:Delayed gross motor development (1)
1	-	-	Deficiency of iodide peroxidase (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D
Eigen	Benign	0.093
Eigen_PC	Benign	-0.071
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.4
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.45
Sift	Benign	0.19	T
Sift4G	Benign	0.11	T
Polyphen		0.99	D
Vest4		0.34
MutPred		0.72		Loss of sheet (P = 0.1158)
MVP		0.83
MPC		0.24
ClinPred		0.83	D
GERP RS		3.4
PromoterAI		-0.0033	Neutral
Varity_R		0.31
gMVP		0.79
Mutation Taster		=90/10	disease causing (ClinVar)

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: rs1057518950; hg19: chr2-1488587; COSMIC: COSV61110083;