17-40083827-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_199334.5(THRA):c.223-8C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00316 in 1,592,578 control chromosomes in the GnomAD database, including 150 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.018 (88 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (62 hom.)
• Consequence: THRA NM_199334.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002827
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.112

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 17-40083827-C-T is Benign according to our data. Variant chr17-40083827-C-T is described in ClinVar as [Benign]. Clinvar id is 781298.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-40083827-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0604 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THRA	NM_199334.5	c.223-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000450525.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THRA	ENST00000450525.7	c.223-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_199334.5	P1

Frequencies

GnomAD3 genomes AF: 0.0177 AC: 2692 AN: 152200 Hom.: 88 Cov.: 32

Gnomad AFR AF: 0.0623

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00491

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00465 AC: 1086 AN: 233736 Hom.: 33 AF XY: 0.00325 AC XY: 410 AN XY: 126022

Gnomad AFR exome AF: 0.0632

Gnomad AMR exome AF: 0.00229

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000110

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000377

Gnomad OTH exome AF: 0.00107

GnomAD4 exome AF: 0.00161 AC: 2324 AN: 1440260 Hom.: 62 Cov.: 30 AF XY: 0.00139 AC XY: 993 AN XY: 715012

Gnomad4 AFR exome AF: 0.0601

Gnomad4 AMR exome AF: 0.00225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000844

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000345

Gnomad4 OTH exome AF: 0.00338

GnomAD4 genome AF: 0.0177 AC: 2702 AN: 152318 Hom.: 88 Cov.: 32 AF XY: 0.0170 AC XY: 1269 AN XY: 74484

Gnomad4 AFR AF: 0.0624

Gnomad4 AMR AF: 0.00490

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00994 Hom.: 11

Bravo AF: 0.0199

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	5.9
Dann	Benign	0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000028
dbscSNV1_RF	Benign	0.0
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: rs78020205; hg19: chr17-38240080;