chr2-1456232-G-T

Variant names:

• chr2-1456232-G-T
• rs4927611
• NM_001206744.2:c.769G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000329066.9(TPO):​c.769G>T​(p.Ala257Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.381 in 1,613,664 control chromosomes in the GnomAD database, including 118,663 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A257T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.38 (11234 hom., cov: 34)
  • Exomes 𝑓: 0.38 (107429 hom.)
• Consequence: TPO ENST00000329066.9 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.754
• Publications: 41 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: Labcorp Genetics (formerly Invitae)
• familial thyroid dyshormonogenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000231482 (HGNC:):

ENSG00000228613 (HGNC:58132):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=2.718866E-4).
• BP6: Variant 2-1456232-G-T is Benign according to our data. Variant chr2-1456232-G-T is described in ClinVar as Benign. ClinVar VariationId is 256616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000329066.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPO	NM_001206744.2	MANE Select	c.769G>T	p.Ala257Ser	missense	Exon 7 of 17	NP_001193673.1
	TPO	NM_000547.6		c.769G>T	p.Ala257Ser	missense	Exon 7 of 17	NP_000538.3
	TPO	NM_175721.3		c.769G>T	p.Ala257Ser	missense	Exon 6 of 15	NP_783652.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPO	ENST00000329066.9	TSL:1 MANE Select	c.769G>T	p.Ala257Ser	missense	Exon 7 of 17	ENSP00000329869.4
	TPO	ENST00000345913.8	TSL:1	c.769G>T	p.Ala257Ser	missense	Exon 7 of 17	ENSP00000318820.7
	TPO	ENST00000382201.7	TSL:1	c.769G>T	p.Ala257Ser	missense	Exon 7 of 16	ENSP00000371636.3

Frequencies

GnomAD3 genomes AF: 0.382 AC: 57959 AN: 151874 Hom.: 11217 Cov.: 34

Gnomad AFR AF: 0.369

Gnomad AMI AF: 0.393

Gnomad AMR AF: 0.414

Gnomad ASJ AF: 0.397

Gnomad EAS AF: 0.184

Gnomad SAS AF: 0.483

Gnomad FIN AF: 0.433

Gnomad MID AF: 0.290

Gnomad NFE AF: 0.381

Gnomad OTH AF: 0.387

GnomAD2 exomes AF: 0.381 AC: 95673 AN: 251118 AF XY: 0.386

Gnomad AFR exome AF: 0.372

Gnomad AMR exome AF: 0.383

Gnomad ASJ exome AF: 0.396

Gnomad EAS exome AF: 0.180

Gnomad FIN exome AF: 0.427

Gnomad NFE exome AF: 0.374

Gnomad OTH exome AF: 0.387

GnomAD4 exome AF: 0.380 AC: 556027 AN: 1461672 Hom.: 107429 Cov.: 70 AF XY: 0.383 AC XY: 278506 AN XY: 727116

African (AFR) AF: 0.376 AC: 12591 AN: 33474

American (AMR) AF: 0.387 AC: 17320 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.394 AC: 10310 AN: 26136

East Asian (EAS) AF: 0.195 AC: 7741 AN: 39696

South Asian (SAS) AF: 0.484 AC: 41712 AN: 86240

European-Finnish (FIN) AF: 0.422 AC: 22492 AN: 53322

Middle Eastern (MID) AF: 0.338 AC: 1950 AN: 5768

European-Non Finnish (NFE) AF: 0.377 AC: 418896 AN: 1111938

Other (OTH) AF: 0.381 AC: 23015 AN: 60386

GnomAD4 genome AF: 0.382 AC: 58021 AN: 151992 Hom.: 11234 Cov.: 34 AF XY: 0.385 AC XY: 28610 AN XY: 74282

African (AFR) AF: 0.369 AC: 15311 AN: 41450

American (AMR) AF: 0.414 AC: 6322 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.397 AC: 1376 AN: 3470

East Asian (EAS) AF: 0.184 AC: 955 AN: 5186

South Asian (SAS) AF: 0.482 AC: 2322 AN: 4814

European-Finnish (FIN) AF: 0.433 AC: 4563 AN: 10532

Middle Eastern (MID) AF: 0.291 AC: 85 AN: 292

European-Non Finnish (NFE) AF: 0.381 AC: 25918 AN: 67960

Other (OTH) AF: 0.385 AC: 813 AN: 2110

Alfa AF: 0.375 Hom.: 32157

Bravo AF: 0.375

TwinsUK AF: 0.381 AC: 1412

ALSPAC AF: 0.376 AC: 1451

ESP6500AA AF: 0.376 AC: 1657

ESP6500EA AF: 0.384 AC: 3302

ExAC AF: 0.379 AC: 46038

Asia WGS AF: 0.364 AC: 1267 AN: 3478

EpiCase AF: 0.376

EpiControl AF: 0.377

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Deficiency of iodide peroxidase (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	6.8
DANN	Benign	0.97
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.00027	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.75
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.069
Sift	Benign	0.052	T
Sift4G	Uncertain	0.044	D
Polyphen		0.056	B
Vest4		0.069
MPC		0.19
ClinPred		0.0088	T
GERP RS		0.49
Varity_R		0.14
gMVP		0.41
Mutation Taster		=98/2	polymorphism (auto)

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: rs4927611; hg19: chr2-1460004; COSMIC: COSV61096637; COSMIC: COSV61096637;