2-1484596-A-T

Position:

• chr2-1484596-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001206744.2(TPO):​c.1339A>T​(p.Ile447Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TPO NM_001206744.2 missense, splice_region
• Scores: Splicing: ADA: 0.6100
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.26

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant 2-1484596-A-T is Pathogenic according to our data. Variant chr2-1484596-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 4043.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPO	NM_001206744.2	c.1339A>T	p.Ile447Phe	missense_variant, splice_region_variant	9/17	ENST00000329066.9	NP_001193673.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPO	ENST00000329066.9	c.1339A>T	p.Ile447Phe	missense_variant, splice_region_variant	9/17	1	NM_001206744.2	ENSP00000329869.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461810 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Deficiency of iodide peroxidase Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 1997

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.75	D;D;.;.;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;.;D;D;T;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D
MetaSVM	Uncertain	-0.0019	T
MutationAssessor	Uncertain	2.8	M;M;M;M;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.5	D;D;D;D;D;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0030	D;D;D;D;T;T
Sift4G	Uncertain	0.013	D;D;D;D;D;T
Polyphen		1.0	D;D;D;D;D;.
Vest4		0.90
MutPred		0.85		Gain of catalytic residue at I447 (P = 0.0197);Gain of catalytic residue at I447 (P = 0.0197);Gain of catalytic residue at I447 (P = 0.0197);Gain of catalytic residue at I447 (P = 0.0197);.;.;
MVP		0.91
MPC		0.85
ClinPred		0.97	D
GERP RS		4.0
Varity_R		0.73
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.61
dbscSNV1_RF	Benign	0.71
SpliceAI score (max)		0.15		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: rs104893669; hg19: chr2-1488368;