17-40093060-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.29

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]

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, THRA
• BP4: Computational evidence support a benign effect (MetaRNN=0.13100341).
• BS2: High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR1D1	NM_021724.5	c.*23G>A		3_prime_UTR_variant	8/8	ENST00000246672.4
THRA	NM_001190919.2	c.1151C>T	p.Ala384Val	missense_variant	10/10
THRA	NM_003250.6	c.1151C>T	p.Ala384Val	missense_variant	10/10
THRA	NM_001190918.2	c.1111-77C>T		intron_variant

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152172 Hom.: 0 Cov.: 32

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: 14 AN: 250880 Hom.: 0 AF XY: 0.0000810 AC XY: 11 AN XY: 135780

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: 20 AN: 1461818 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 727212

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: 6 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74342

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: 7

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.090
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.34	T;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.077
FATHMM_MKL	Uncertain	0.76	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	D;N;N;D
PrimateAI	Uncertain	0.62	T
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	T
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

Other links and lift over

dbSNP: rs202143691; hg19: chr17-38249313; COSMIC: COSV105852277; COSMIC: COSV105852277;