ENST00000578218.5:c.-326G>A

Variant names:

• chr17-40062520-G-A
• rs62065216
• ENST00000578218.5:c.-326G>A

Variant summary

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

The ENST00000578218.5(THRA):​c.-326G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.377 in 151,884 control chromosomes in the GnomAD database, including 11,305 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 0.38 (11303 hom., cov: 30)
  • Exomes 𝑓: 0.39 (2 hom.)
• Consequence: THRA ENST00000578218.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.81
• Publications: 15 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=-0.75).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.527 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000578218.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THRA	NM_001190919.2		c.-298+69G>A		intron	N/A	NP_001177848.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THRA	ENST00000578218.5	TSL:4	c.-326G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	ENSP00000464123.1
	THRA	ENST00000578218.5	TSL:4	c.-326G>A		5_prime_UTR	Exon 1 of 5	ENSP00000464123.1
	THRA	ENST00000394121.8	TSL:2	c.-298+69G>A		intron	N/A	ENSP00000377679.4

Frequencies

GnomAD3 genomes AF: 0.377 AC: 57130 AN: 151738 Hom.: 11284 Cov.: 30

Gnomad AFR AF: 0.263

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.367

Gnomad ASJ AF: 0.339

Gnomad EAS AF: 0.544

Gnomad SAS AF: 0.270

Gnomad FIN AF: 0.490

Gnomad MID AF: 0.255

Gnomad NFE AF: 0.427

Gnomad OTH AF: 0.365

GnomAD4 exome AF: 0.393 AC: 11 AN: 28 Hom.: 2 Cov.: 0 AF XY: 0.450 AC XY: 9 AN XY: 20

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.333 AC: 4 AN: 12

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.438 AC: 7 AN: 16

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.377 AC: 57181 AN: 151856 Hom.: 11303 Cov.: 30 AF XY: 0.377 AC XY: 27956 AN XY: 74178

African (AFR) AF: 0.263 AC: 10887 AN: 41408

American (AMR) AF: 0.368 AC: 5618 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.339 AC: 1176 AN: 3468

East Asian (EAS) AF: 0.544 AC: 2796 AN: 5138

South Asian (SAS) AF: 0.271 AC: 1305 AN: 4812

European-Finnish (FIN) AF: 0.490 AC: 5158 AN: 10534

Middle Eastern (MID) AF: 0.264 AC: 77 AN: 292

European-Non Finnish (NFE) AF: 0.427 AC: 29025 AN: 67924

Other (OTH) AF: 0.368 AC: 777 AN: 2114

Alfa AF: 0.399 Hom.: 2754

Bravo AF: 0.363

Asia WGS AF: 0.398 AC: 1382 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	16
DANN	Benign	0.89
PhyloP100		1.8
PromoterAI		-0.043	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs62065216; hg19: chr17-38218773;