Genetic Variant TPO:c.2387-17C>T (chr2-1503931-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001206744.2(TPO):c.2387-17C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00249 in 1,614,126 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0035 ( 10 hom., cov: 33)

Exomes 𝑓: 0.0024 ( 77 hom. )

Consequence

TPO
NM_001206744.2 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.535

Publications

2 publications found

Variant links:

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

TPO links:

ENSG00000231482 (HGNC:):

ENSG00000231482 links:

LALTOP (HGNC:58132):

LALTOP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 2-1503931-C-T is Benign according to our data. Variant chr2-1503931-C-T is described in ClinVar as Benign. ClinVar VariationId is 256613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00353 (538/152296) while in subpopulation EAS AF = 0.0414 (214/5164). AF 95% confidence interval is 0.0369. There are 10 homozygotes in GnomAd4. There are 305 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TPO	NM_001206744.2	MANE Select	c.2387-17C>T	intron	N/A	NP_001193673.1	P07202-1
TPO	NM_000547.6		c.2387-17C>T	intron	N/A	NP_000538.3
TPO	NM_175721.3		c.2386+7166C>T	intron	N/A	NP_783652.1	P07202-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TPO	ENST00000329066.9	TSL:1 MANE Select	c.2387-17C>T	intron	N/A	ENSP00000329869.4	P07202-1
TPO	ENST00000345913.8	TSL:1	c.2387-17C>T	intron	N/A	ENSP00000318820.7	P07202-1
TPO	ENST00000382201.7	TSL:1	c.2216-17C>T	intron	N/A	ENSP00000371636.3	P07202-2

Frequencies

GnomAD3 genomes

AF:

0.00353

AC:

537

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0179

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.0413

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00774

AC:

1943

AN:

251192

AF XY:

0.00667

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.0310

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.0425

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000617

Gnomad OTH exome

AF:

0.00457

GnomAD4 exome

AF:

0.00239

AC:

3488

AN:

1461830

Hom.:

Cov.:

AF XY:

0.00230

AC XY:

1670

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33480

American (AMR)

AF:

0.0302

AC:

1351

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000421

AC:

AN:

26136

East Asian (EAS)

AF:

0.0461

AC:

1829

AN:

39700

South Asian (SAS)

AF:

0.00139

AC:

120

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000243

AC:

AN:

1111988

Other (OTH)

AF:

0.00233

AC:

141

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

219

437

656

874

1093

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00353

AC:

538

AN:

152296

Hom.:

Cov.:

AF XY:

0.00410

AC XY:

305

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.000529

AC:

AN:

41564

American (AMR)

AF:

0.0180

AC:

275

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.000577

AC:

AN:

3468

East Asian (EAS)

AF:

0.0414

AC:

214

AN:

5164

South Asian (SAS)

AF:

0.00249

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68034

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

105

131

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00174

Hom.:

Bravo

AF:

0.00513

Asia WGS

AF:

0.0110

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.0

(source)

DANN

Benign

0.47

PhyloP100

0.54

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over