chr2-1487991-G-C

Variant names:

• chr2-1487991-G-C
• rs121908084
• NM_001206744.2:c.1768G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_001206744.2(TPO):​c.1768G>C​(p.Gly590Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000657 in 152,200 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 predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G590S) has been classified as Pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: TPO NM_001206744.2 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.41
• Publications: 8 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: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• familial thyroid dyshormonogenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000231482 (HGNC:):

LALTOP (HGNC:58132):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-1487991-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 4045.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.1768G>C	p.Gly590Arg	missense splice_region	Exon 10 of 17	NP_001193673.1	P07202-1
	TPO	NM_000547.6		c.1768G>C	p.Gly590Arg	missense splice_region	Exon 10 of 17	NP_000538.3
	TPO	NM_175721.3		c.1768G>C	p.Gly590Arg	missense splice_region	Exon 9 of 15	NP_783652.1	P07202-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPO	ENST00000329066.9	TSL:1 MANE Select	c.1768G>C	p.Gly590Arg	missense splice_region	Exon 10 of 17	ENSP00000329869.4	P07202-1
	TPO	ENST00000345913.8	TSL:1	c.1768G>C	p.Gly590Arg	missense splice_region	Exon 10 of 17	ENSP00000318820.7	P07202-1
	TPO	ENST00000382198.5	TSL:1	c.1249G>C	p.Gly417Arg	missense splice_region	Exon 8 of 15	ENSP00000371633.1	P07202-5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74348

African (AFR) AF: 0.0000241 AC: 1 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		5.4
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.034	D
Polyphen		1.0	D
Vest4		0.54
MutPred		0.65		Gain of solvent accessibility (P = 0.0789)
MVP		0.92
MPC		0.74
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.77
gMVP		0.92
Mutation Taster		=9/91	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.81		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.81		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121908084; hg19: chr2-1491763;