rs104893669

Positions:

• chr2-1484596-A-G
• chr2-1484596-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001206744.2(TPO):​c.1339A>G​(p.Ile447Val) 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. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TPO NM_001206744.2 missense, splice_region
• Scores: Splicing: ADA: 0.0003566
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPO	NM_001206744.2	c.1339A>G	p.Ile447Val	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>G	p.Ile447Val	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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.31	T;T;.;.;.;.
Eigen	Benign	-0.052
Eigen_PC	Benign	0.021
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.79	T;.;T;T;T;T
M_CAP	Benign	0.076	D
MetaRNN	Uncertain	0.55	D;D;D;D;T;D
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.3	L;L;L;L;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.61	N;N;N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.14	T;T;T;T;T;T
Sift4G	Benign	0.28	T;T;T;T;T;T
Polyphen		0.48	P;P;B;B;P;.
Vest4		0.13
MutPred		0.73		Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);.;.;
MVP		0.77
MPC		0.28
ClinPred		0.33	T
GERP RS		4.0
Varity_R		0.096
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00036
dbscSNV1_RF	Benign	0.016
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: rs104893669; hg19: chr2-1488368;