rs28912996

Positions:

• chr2-1503931-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001206744.2(TPO):​c.2387-17C>T variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.535

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 256613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-1503931-C-T is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPO	NM_001206744.2	c.2387-17C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000329066.9
LOC124905966	XR_007086185.1	n.167-17740G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPO	ENST00000329066.9	c.2387-17C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001206744.2	P1
	ENST00000650512.1	n.547+76270G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00353 AC: 537 AN: 152178 Hom.: 10 Cov.: 33

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

GnomAD3 exomes AF: 0.00774 AC: 1943 AN: 251192 Hom.: 43 AF XY: 0.00667 AC XY: 906 AN XY: 135810

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 SAS exome AF: 0.00137

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.: 77 Cov.: 31 AF XY: 0.00230 AC XY: 1670 AN XY: 727212

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.0302

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.0461

Gnomad4 SAS exome AF: 0.00139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.00233

GnomAD4 genome AF: 0.00353 AC: 538 AN: 152296 Hom.: 10 Cov.: 33 AF XY: 0.00410 AC XY: 305 AN XY: 74468

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.0180

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.0414

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00131 Hom.: 0

Bravo AF: 0.00513

Asia WGS AF: 0.0110 AC: 39 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.0
DANN	Benign	0.47

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

LitVar

Other links and lift over

dbSNP: rs28912996; hg19: chr2-1507703;