chr2-1494027-G-A

Variant names:

• chr2-1494027-G-A
• rs140124953
• NM_001206744.2:c.1994G>A

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_001206744.2(TPO):​c.1994G>A​(p.Arg665Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,461,770 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 (★★). ClinVar reports functional evidence for this variant: "SCV004292048: Experimental studies have shown that this missense change affects TPO function (PMID:32078117).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R665W) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TPO NM_001206744.2 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.31
• 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: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004292048: Experimental studies have shown that this missense change affects TPO function (PMID: 32078117).
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001206744.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-1494026-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2734130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.906
• PP5: Variant 2-1494027-G-A is Pathogenic according to our data. Variant chr2-1494027-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 374344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.1994G>A	p.Arg665Gln	missense	Exon 11 of 17	NP_001193673.1	P07202-1
	TPO	NM_000547.6		c.1994G>A	p.Arg665Gln	missense	Exon 11 of 17	NP_000538.3
	TPO	NM_175721.3		c.1994G>A	p.Arg665Gln	missense	Exon 10 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.1994G>A	p.Arg665Gln	missense	Exon 11 of 17	ENSP00000329869.4	P07202-1
	TPO	ENST00000345913.8	TSL:1	c.1994G>A	p.Arg665Gln	missense	Exon 11 of 17	ENSP00000318820.7	P07202-1
	TPO	ENST00000382201.7	TSL:1	c.1823G>A	p.Arg608Gln	missense	Exon 10 of 16	ENSP00000371636.3	P07202-2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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

GnomAD2 exomes AF: 0.0000279 AC: 7 AN: 250664 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461770 Hom.: 0 Cov.: 33 AF XY: 0.0000220 AC XY: 16 AN XY: 727178

African (AFR) AF: 0.00 AC: 0 AN: 33478

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

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111954

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 152162 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74332

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000194 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Deficiency of iodide peroxidase (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.3
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MVP		0.92
MPC		0.73
ClinPred		0.97	D
GERP RS		4.8
Varity_R		0.89
gMVP		0.91
Mutation Taster		=1/99	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: rs140124953; hg19: chr2-1497799;