Genetic Variant THRA:p.Ala117Ala (chr17-40083963-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_199334.5(THRA):c.351C>T(p.Ala117Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0447 in 1,613,222 control chromosomes in the GnomAD database, including 1,869 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.040 ( 151 hom., cov: 32)

Exomes 𝑓: 0.045 ( 1718 hom. )

Consequence

THRA
NM_199334.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -5.76

Publications

10 publications found

Variant links:

Genes affected

THRA (HGNC:11796): (thyroid hormone receptor alpha) The protein encoded by this gene is a nuclear hormone receptor for triiodothyronine. It is one of the several receptors for thyroid hormone, and has been shown to mediate the biological activities of thyroid hormone. Knockout studies in mice suggest that the different receptors, while having certain extent of redundancy, may mediate different functions of thyroid hormone. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

THRA Gene-Disease associations (from GenCC):

congenital nongoitrous hypothyroidism 6
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

THRA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.31).

BP6

Variant 17-40083963-C-T is Benign according to our data. Variant chr17-40083963-C-T is described in ClinVar as [Benign]. Clinvar id is 259020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-5.76 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0395 (6022/152266) while in subpopulation NFE AF = 0.0482 (3280/68004). AF 95% confidence interval is 0.0469. There are 151 homozygotes in GnomAd4. There are 2796 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 6022 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THRA	NM_199334.5 link	c.351C>T	p.Ala117Ala	synonymous_variant	Exon 5 of 9	ENST00000450525.7	NP_955366.1	P10827-2Q6FH41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THRA	ENST00000450525.7 link	c.351C>T	p.Ala117Ala	synonymous_variant	Exon 5 of 9	1	NM_199334.5	ENSP00000395641.3		P10827-2

Frequencies

GnomAD3 genomes

AF:

0.0394

AC:

6002

AN:

152148

Hom.:

147

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0381

Gnomad AMI

AF:

0.0318

Gnomad AMR

AF:

0.0240

Gnomad ASJ

AF:

0.0144

Gnomad EAS

AF:

0.00539

Gnomad SAS

AF:

0.0254

Gnomad FIN

AF:

0.0439

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0482

Gnomad OTH

AF:

0.0363

GnomAD2 exomes

AF:

0.0365

AC:

9131

AN:

250440

AF XY:

0.0361

show subpopulations

Gnomad AFR exome

AF:

0.0396

Gnomad AMR exome

AF:

0.0182

Gnomad ASJ exome

AF:

0.0181

Gnomad EAS exome

AF:

0.00802

Gnomad FIN exome

AF:

0.0435

Gnomad NFE exome

AF:

0.0468

Gnomad OTH exome

AF:

0.0371

GnomAD4 exome

AF:

0.0452

AC:

66057

AN:

1460956

Hom.:

1718

Cov.:

AF XY:

0.0443

AC XY:

32173

AN XY:

726788

show subpopulations

African (AFR)

AF:

0.0411

AC:

1375

AN:

33446

American (AMR)

AF:

0.0194

AC:

866

AN:

44644

Ashkenazi Jewish (ASJ)

AF:

0.0177

AC:

462

AN:

26092

East Asian (EAS)

AF:

0.00358

AC:

142

AN:

39642

South Asian (SAS)

AF:

0.0324

AC:

2788

AN:

86142

European-Finnish (FIN)

AF:

0.0463

AC:

2475

AN:

53400

Middle Eastern (MID)

AF:

0.0116

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0498

AC:

55372

AN:

1111474

Other (OTH)

AF:

0.0416

AC:

2510

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

3589

7177

10766

14354

17943

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0395

AC:

6022

AN:

152266

Hom.:

151

Cov.:

AF XY:

0.0376

AC XY:

2796

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.0385

AC:

1599

AN:

41562

American (AMR)

AF:

0.0240

AC:

367

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0144

AC:

AN:

3472

East Asian (EAS)

AF:

0.00541

AC:

AN:

5178

South Asian (SAS)

AF:

0.0255

AC:

123

AN:

4832

European-Finnish (FIN)

AF:

0.0439

AC:

466

AN:

10606

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0482

AC:

3280

AN:

68004

Other (OTH)

AF:

0.0360

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

305

610

915

1220

1525

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0434

Hom.:

169

Bravo

AF:

0.0383

Asia WGS

AF:

0.0420

AC:

145

AN:

3478

EpiCase

AF:

0.0415

EpiControl

AF:

0.0412

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 18, 2016

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.72

PhyloP100

-5.8

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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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17-40083963-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over