chr17-40093023-A-G

Variant names:

• chr17-40093023-A-G
• ENST00000264637.8:c.1114A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_003250.6(THRA):​c.1114A>G​(p.Arg372Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: THRA NM_003250.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.07

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the THRA gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 3.4693 (above the threshold of 3.09). Trascript score misZ: 4.2669 (above the threshold of 3.09). GenCC associations: The gene is linked to congenital nongoitrous hypothryoidism 6.
• BP4: Computational evidence support a benign effect (MetaRNN=0.25661284).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1D1	NM_021724.5	c.*60T>C		3_prime_UTR_variant	Exon 8 of 8	ENST00000246672.4	NP_068370.1
THRA	NM_199334.5	c.*3567A>G		downstream_gene_variant		ENST00000450525.7	NP_955366.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR1D1	ENST00000246672	c.*60T>C		3_prime_UTR_variant	Exon 8 of 8	1	NM_021724.5	ENSP00000246672.3
THRA	ENST00000450525.7	c.*3567A>G		downstream_gene_variant		1	NM_199334.5	ENSP00000395641.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457974 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724366

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.42	T;T
Eigen	Benign	-0.097
Eigen_PC	Benign	0.072
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.63	.;T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Uncertain	0.071	D
MutationAssessor	Benign	0.34	N;N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.92	N;N
REVEL	Uncertain	0.56
Sift	Benign	0.055	T;T
Sift4G	Benign	0.23	T;T
Polyphen		0.065	B;B
Vest4		0.26
MutPred		0.63		Loss of MoRF binding (P = 0.0538);Loss of MoRF binding (P = 0.0538);
MVP		0.95
MPC		1.3
ClinPred		0.53	D
GERP RS		4.9
Varity_R		0.091
gMVP		0.60

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-38249276;