17-40075600-T-C

Variant names:

• chr17-40075600-T-C
• rs939348
• NM_199334.5:c.53+1059T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_199334.5(THRA):​c.53+1059T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.698 in 152,158 control chromosomes in the GnomAD database, including 37,420 homozygotes. 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: 𝑓 0.70 (37420 hom., cov: 33)
• Consequence: THRA NM_199334.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.389
• Publications: 23 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.714 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THRA	NM_199334.5	MANE Select	c.53+1059T>C		intron	N/A	NP_955366.1	Q6FH41
	THRA	NM_001190919.2		c.53+1059T>C		intron	N/A	NP_001177848.1	P10827-1
	THRA	NM_003250.6		c.53+1059T>C		intron	N/A	NP_003241.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THRA	ENST00000450525.7	TSL:1 MANE Select	c.53+1059T>C		intron	N/A	ENSP00000395641.3	P10827-2
	THRA	ENST00000264637.8	TSL:1	c.53+1059T>C		intron	N/A	ENSP00000264637.4	P10827-1
	THRA	ENST00000584985.5	TSL:1	c.53+1059T>C		intron	N/A	ENSP00000463466.1	P10827-3

Frequencies

GnomAD3 genomes AF: 0.698 AC: 106199 AN: 152040 Hom.: 37403 Cov.: 33

Gnomad AFR AF: 0.711

Gnomad AMI AF: 0.682

Gnomad AMR AF: 0.710

Gnomad ASJ AF: 0.738

Gnomad EAS AF: 0.381

Gnomad SAS AF: 0.696

Gnomad FIN AF: 0.639

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.720

Gnomad OTH AF: 0.710

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.698 AC: 106260 AN: 152158 Hom.: 37420 Cov.: 33 AF XY: 0.694 AC XY: 51646 AN XY: 74382

African (AFR) AF: 0.711 AC: 29534 AN: 41510

American (AMR) AF: 0.709 AC: 10838 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.738 AC: 2561 AN: 3470

East Asian (EAS) AF: 0.380 AC: 1969 AN: 5176

South Asian (SAS) AF: 0.695 AC: 3356 AN: 4828

European-Finnish (FIN) AF: 0.639 AC: 6769 AN: 10596

Middle Eastern (MID) AF: 0.704 AC: 207 AN: 294

European-Non Finnish (NFE) AF: 0.720 AC: 48910 AN: 67966

Other (OTH) AF: 0.708 AC: 1495 AN: 2112

Alfa AF: 0.710 Hom.: 81610

Bravo AF: 0.704

Asia WGS AF: 0.568 AC: 1979 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	3.2
DANN	Benign	0.54
PhyloP100		-0.39
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs939348; hg19: chr17-38231853;