17-40083830-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_199334.5(THRA):c.223-5C>G 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 0.000652 in 1,598,514 control chromosomes in the GnomAD database, including 7 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 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (7 hom.)
• Consequence: THRA NM_199334.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.009263
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.265

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 17-40083830-C-G is Benign according to our data. Variant chr17-40083830-C-G is described in ClinVar as [Benign]. Clinvar id is 723441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 68 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THRA	NM_199334.5	c.223-5C>G		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.223-5C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_199334.5	P1

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 68 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00125 AC: 297 AN: 237878 Hom.: 1 AF XY: 0.00168 AC XY: 215 AN XY: 128166

Gnomad AFR exome AF: 0.0000628

Gnomad AMR exome AF: 0.00137

Gnomad ASJ exome AF: 0.000883

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00670

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000446

Gnomad OTH exome AF: 0.00139

GnomAD4 exome AF: 0.000673 AC: 974 AN: 1446200 Hom.: 7 Cov.: 30 AF XY: 0.000874 AC XY: 628 AN XY: 718520

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00131

Gnomad4 ASJ exome AF: 0.000518

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.00647

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000264

Gnomad4 OTH exome AF: 0.000853

GnomAD4 genome AF: 0.000453 AC: 69 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.000564 AC XY: 42 AN XY: 74482

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000608 Hom.: 0

Bravo AF: 0.000336

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 10, 2018

- -

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	-0.73
Cadd	Benign	7.9
Dann	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0093
dbscSNV1_RF	Benign	0.086
SpliceAI score (max)		0.060		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: rs200727359; hg19: chr17-38240083;