17-40093060-C-T

Position:

chr17-40093060-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM1PP2BP4_ModerateBS2

The ENST00000264637.8(THRA):c.1151C>T(p.Ala384Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,613,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

THRA
ENST00000264637.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.29

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:

NR1D1 (HGNC:7962): (nuclear receptor subfamily 1 group D member 1) This gene encodes a transcription factor that is a member of the nuclear receptor subfamily 1. The encoded protein is a ligand-sensitive transcription factor that negatively regulates the expression of core clock proteins. In particular this protein represses the circadian clock transcription factor aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL). This protein may also be involved in regulating genes that function in metabolic, inflammatory and cardiovascular processes. [provided by RefSeq, Jan 2013]

NR1D1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1

In a domain NR LBD (size 244) in uniprot entity THA_HUMAN there are 9 pathogenic changes around while only 2 benign (82%) in ENST00000264637.8

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), THRA. . Gene score misZ 3.4693 (greater than the threshold 3.09). Trascript score misZ 4.2669 (greater than threshold 3.09). GenCC has associacion of gene with congenital nongoitrous hypothryoidism 6.

BP4

Computational evidence support a benign effect (MetaRNN=0.13100341).

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NR1D1	NM_021724.5 linkuse as main transcript	c.*23G>A		3_prime_UTR_variant	8/8	ENST00000246672.4	NP_068370.1
THRA	NM_001190919.2 linkuse as main transcript	c.1151C>T	p.Ala384Val	missense_variant	10/10		NP_001177848.1
THRA	NM_003250.6 linkuse as main transcript	c.1151C>T	p.Ala384Val	missense_variant	10/10		NP_003241.2
THRA	NM_001190918.2 linkuse as main transcript	c.1111-77C>T		intron_variant			NP_001177847.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THRA	ENST00000264637.8 linkuse as main transcript	c.1151C>T	p.Ala384Val	missense_variant	10/10	1		ENSP00000264637		P10827-1
NR1D1	ENST00000246672.4 linkuse as main transcript	c.*23G>A		3_prime_UTR_variant	8/8	1	NM_021724.5	ENSP00000246672	P1
THRA	ENST00000584985.5 linkuse as main transcript	c.1111-77C>T		intron_variant		1		ENSP00000463466		P10827-3
THRA	ENST00000394121.8 linkuse as main transcript	c.1151C>T	p.Ala384Val	missense_variant	10/10	2		ENSP00000377679		P10827-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000558

AC:

AN:

250880

Hom.:

AF XY:

0.0000810

AC XY:

AN XY:

135780

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461818

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000567

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 15, 2021

The c.1151C>T (p.A384V) alteration is located in exon 10 (coding exon 9) of the THRA gene. This alteration results from a C to T substitution at nucleotide position 1151, causing the alanine (A) at amino acid position 384 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.34

T;T

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.077

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.71

.;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-0.30

MutationAssessor

Benign

0.0

N;N

MutationTaster

Benign

1.0

D;N;N;D

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.46

N;N

REVEL

Uncertain

0.30

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

0.052

B;B

Vest4

0.25

MutPred

0.35

Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);

MVP

0.90

MPC

1.9

ClinPred

0.078

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.083

gMVP

0.23

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

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