Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_199334.5(THRA):c.577-4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000917 in 1,613,744 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00065 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00094 ( 1 hom. )

Consequence

THRA
NM_199334.5 splice_region, intron

Scores

Splicing: ADA: 0.00001025

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -3.73

Publications

0 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 17-40086703-C-T is Benign according to our data. Variant chr17-40086703-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 437003.

BS2

High AC in GnomAd4 at 99 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199334.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
THRA	NM_199334.5	MANE Select	c.577-4C>T	splice_region intron	N/A	NP_955366.1
THRA	NM_001190919.2		c.577-4C>T	splice_region intron	N/A	NP_001177848.1
THRA	NM_003250.6		c.577-4C>T	splice_region intron	N/A	NP_003241.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
THRA	ENST00000450525.7	TSL:1 MANE Select	c.577-4C>T	splice_region intron	N/A	ENSP00000395641.3
THRA	ENST00000264637.8	TSL:1	c.577-4C>T	splice_region intron	N/A	ENSP00000264637.4
THRA	ENST00000584985.5	TSL:1	c.577-4C>T	splice_region intron	N/A	ENSP00000463466.1

Frequencies

GnomAD3 genomes

AF:

0.000651

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00115

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000765

AC:

192

AN:

250828

AF XY:

0.000922

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000988

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.000945

AC:

1381

AN:

1461452

Hom.:

Cov.:

AF XY:

0.000953

AC XY:

693

AN XY:

726978

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33474

American (AMR)

AF:

0.000336

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00133

AC:

115

AN:

86240

European-Finnish (FIN)

AF:

0.000468

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00434

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00103

AC:

1145

AN:

1111702

Other (OTH)

AF:

0.000812

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

152

229

305

381

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

132

176

220

<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:

0.000650

AC:

AN:

152292

Hom.:

Cov.:

AF XY:

0.000604

AC XY:

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41548

American (AMR)

AF:

0.0000653

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00166

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00115

AC:

AN:

68020

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000780

Hom.:

Bravo

AF:

0.000480

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000872

EpiControl

AF:

0.00148

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

THRA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

1.1

(source)

DANN

Benign

0.65

PhyloP100

-3.7

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000010

dbscSNV1_RF

Benign

0.0040

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs188965373

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over