NM_199334.5:c.223-8C>T

Variant names:

• chr17-40083827-C-T
• rs78020205
• NM_199334.5:c.223-8C>T

Variant summary

Our verdict is Benign. The variant received -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, 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, intron
• Scores: Splicing: ADA: 0.00002827
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.112
• Publications: 0 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 -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.
• 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 rank	MANE	Protein	UniProt
THRA	NM_199334.5	c.223-8C>T		splice_region_variant, intron_variant	Intron 4 of 8	ENST00000450525.7	NP_955366.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THRA	ENST00000450525.7	c.223-8C>T		splice_region_variant, intron_variant	Intron 4 of 8	1	NM_199334.5	ENSP00000395641.3

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

GnomAD2 exomes AF: 0.00465 AC: 1086 AN: 233736 AF XY: 0.00325

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 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

African (AFR) AF: 0.0601 AC: 1976 AN: 32900

American (AMR) AF: 0.00225 AC: 96 AN: 42736

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24828

East Asian (EAS) AF: 0.00 AC: 0 AN: 39024

South Asian (SAS) AF: 0.0000844 AC: 7 AN: 82898

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52712

Middle Eastern (MID) AF: 0.00106 AC: 6 AN: 5666

European-Non Finnish (NFE) AF: 0.0000345 AC: 38 AN: 1099966

Other (OTH) AF: 0.00338 AC: 201 AN: 59530

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

African (AFR) AF: 0.0624 AC: 2592 AN: 41542

American (AMR) AF: 0.00490 AC: 75 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68032

Other (OTH) AF: 0.0104 AC: 22 AN: 2116

Alfa AF: 0.00934 Hom.: 15

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

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.9
DANN	Benign	0.59
PhyloP100		0.11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs78020205; hg19: chr17-38240080;