rs199530759

Positions:

chr17-40076870-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PVS1_ModerateBP6BS2

The ENST00000450525.7(THRA):c.54-1G>A variant causes a splice acceptor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000514 in 1,614,024 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

THRA
ENST00000450525.7 splice_acceptor

Scores

Splicing: ADA: 1.000

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 1.73

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.05433901 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8, offset of 6, new splice context is: ttgcctccatccaatgccAGgtc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

BP6

Variant 17-40076870-G-A is Benign according to our data. Variant chr17-40076870-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 561132.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.

BS2

High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THRA	NM_199334.5 linkuse as main transcript	c.54-1G>A		splice_acceptor_variant		ENST00000450525.7	NP_955366.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THRA	ENST00000450525.7 linkuse as main transcript	c.54-1G>A		splice_acceptor_variant		1	NM_199334.5	ENSP00000395641	P1	P10827-2

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000875

AC:

AN:

251390

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000499

AC:

AN:

1461820

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00126

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000243

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000270

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 16, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 07, 2023	Canonical splice site variant in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31589614) -

Congenital nongoitrous hypothyroidism 6

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

THRA-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 19, 2023

The THRA c.54-1G>A variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant was identified in a population study of recessive conditions (Table S1, Capalbo et al 2019. PubMed ID: 31589614), but to our knowledge has not been reported in an individuals with thyroid hormone resistance phenotype. In ClinVar, few canonical splice site variants have been reported in THRA. Careful analysis of the predicted splice effect using prediction algorithms suggest this variant may result in the activation of a cryptic splice acceptor site that results in an in-frame deletion, although such predictions are not equivalent to functional evidence (Alamut Visual Plus v1.6.1). This variant is reported in 0.12% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-38233123-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.030

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

DANN

Uncertain

0.98

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Uncertain

0.82

MutationTaster

Benign

1.0

D;D;D;D;D

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.97

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.89

Position offset: 7

DS_AL_spliceai

0.97

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over