dbSNP rs78020205: THRA:c.223-8C>T (chr17-40083827-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_199334.5(THRA):c.223-8C>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 0.00316 in 1,592,578 control chromosomes in the GnomAD database, including 150 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 Benign (★).

Frequency

Genomes: 𝑓 0.018 ( 88 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 62 hom. )

Consequence

THRA
NM_199334.5 splice_region, intron

Scores

Splicing: ADA: 0.00002827

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.112

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: PanelApp Australia, 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 17-40083827-C-T is Benign according to our data. Variant chr17-40083827-C-T is described in ClinVar as Benign. ClinVar VariationId is 781298.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0604 is higher than 0.05.

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	UniProt
THRA	NM_199334.5	MANE Select	c.223-8C>T	splice_region intron	N/A	NP_955366.1	Q6FH41
THRA	NM_001190919.2		c.223-8C>T	splice_region intron	N/A	NP_001177848.1	P10827-1
THRA	NM_003250.6		c.223-8C>T	splice_region intron	N/A	NP_003241.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
THRA	ENST00000450525.7	TSL:1 MANE Select	c.223-8C>T	splice_region intron	N/A	ENSP00000395641.3	P10827-2
THRA	ENST00000264637.8	TSL:1	c.223-8C>T	splice_region intron	N/A	ENSP00000264637.4	P10827-1
THRA	ENST00000584985.5	TSL:1	c.223-8C>T	splice_region intron	N/A	ENSP00000463466.1	P10827-3

Frequencies

GnomAD3 genomes

AF:

0.0177

AC:

2692

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0623

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00491

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.00465

AC:

1086

AN:

233736

AF XY:

0.00325

show subpopulations

Gnomad AFR exome

AF:

0.0632

Gnomad AMR exome

AF:

0.00229

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000377

Gnomad OTH exome

AF:

0.00107

GnomAD4 exome

AF:

0.00161

AC:

2324

AN:

1440260

Hom.:

Cov.:

AF XY:

0.00139

AC XY:

993

AN XY:

715012

show subpopulations

African (AFR)

AF:

0.0601

AC:

1976

AN:

32900

American (AMR)

AF:

0.00225

AC:

AN:

42736

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24828

East Asian (EAS)

AF:

0.00

AC:

AN:

39024

South Asian (SAS)

AF:

0.0000844

AC:

AN:

82898

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52712

Middle Eastern (MID)

AF:

0.00106

AC:

AN:

5666

European-Non Finnish (NFE)

AF:

0.0000345

AC:

AN:

1099966

Other (OTH)

AF:

0.00338

AC:

201

AN:

59530

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

106

211

317

422

528

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

186

248

310

<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:

0.0177

AC:

2702

AN:

152318

Hom.:

Cov.:

AF XY:

0.0170

AC XY:

1269

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.0624

AC:

2592

AN:

41542

American (AMR)

AF:

0.00490

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000621

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68032

Other (OTH)

AF:

0.0104

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

129

258

386

515

644

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.00934

Hom.:

Bravo

AF:

0.0199

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

5.9

(source)

DANN

Benign

0.59

PhyloP100

0.11

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000028

dbscSNV1_RF

Benign

0.0

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