NM_199334.5:c.*2645C>T

Variant names:

• chr17-40092101-C-T
• rs3744805
• NM_199334.5:c.*2645C>T

Variant summary

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

The NM_199334.5(THRA):​c.*2645C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 152,012 control chromosomes in the GnomAD database, including 3,618 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 0.20 (3614 hom., cov: 30)
  • Exomes 𝑓: 0.088 (4 hom.)
• Consequence: THRA NM_199334.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.86
• Publications: 16 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: 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=-0.53).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.556 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THRA	NM_199334.5	c.*2645C>T		3_prime_UTR_variant	Exon 9 of 9	ENST00000450525.7	NP_955366.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THRA	ENST00000450525.7	c.*2645C>T		3_prime_UTR_variant	Exon 9 of 9	1	NM_199334.5	ENSP00000395641.3
THRA	ENST00000264637.8	c.1111-919C>T		intron_variant	Intron 9 of 9	1		ENSP00000264637.4
THRA	ENST00000584985.5	c.1111-1036C>T		intron_variant	Intron 9 of 9	1		ENSP00000463466.1
THRA	ENST00000394121.8	c.1111-919C>T		intron_variant	Intron 9 of 9	2		ENSP00000377679.4

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29575 AN: 151620 Hom.: 3608 Cov.: 30

Gnomad AFR AF: 0.273

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.573

Gnomad SAS AF: 0.173

Gnomad FIN AF: 0.194

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.176

GnomAD4 exome AF: 0.0880 AC: 25 AN: 284 Hom.: 4 Cov.: 0 AF XY: 0.0901 AC XY: 20 AN XY: 222

African (AFR) AF: 0.500 AC: 2 AN: 4

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.375 AC: 3 AN: 8

South Asian (SAS) AF: 0.167 AC: 3 AN: 18

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.0588 AC: 14 AN: 238

Other (OTH) AF: 0.250 AC: 3 AN: 12

GnomAD4 genome AF: 0.195 AC: 29615 AN: 151728 Hom.: 3614 Cov.: 30 AF XY: 0.200 AC XY: 14857 AN XY: 74160

African (AFR) AF: 0.273 AC: 11277 AN: 41362

American (AMR) AF: 0.216 AC: 3296 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 566 AN: 3466

East Asian (EAS) AF: 0.574 AC: 2941 AN: 5126

South Asian (SAS) AF: 0.174 AC: 837 AN: 4806

European-Finnish (FIN) AF: 0.194 AC: 2052 AN: 10570

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.119 AC: 8063 AN: 67838

Other (OTH) AF: 0.175 AC: 368 AN: 2102

Alfa AF: 0.140 Hom.: 2406

Bravo AF: 0.201

Asia WGS AF: 0.323 AC: 1119 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Benign	0.92
PhyloP100		1.9
Mutation Taster		=96/4	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: rs3744805; hg19: chr17-38248354;