rs2230701

Variant names:

• chr17-40083963-C-T
• rs2230701
• NM_199334.5:c.351C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_199334.5(THRA):​c.351C>T​(p.Ala117Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0447 in 1,613,222 control chromosomes in the GnomAD database, including 1,869 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (151 hom., cov: 32)
  • Exomes 𝑓: 0.045 (1718 hom.)
• Consequence: THRA NM_199334.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -5.76
• Publications: 10 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 17-40083963-C-T is Benign according to our data. Variant chr17-40083963-C-T is described in ClinVar as Benign. ClinVar VariationId is 259020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.76 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0395 (6022/152266) while in subpopulation NFE AF = 0.0482 (3280/68004). AF 95% confidence interval is 0.0469. There are 151 homozygotes in GnomAd4. There are 2796 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 6022 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199334.5. 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_199334.5	MANE Select	c.351C>T	p.Ala117Ala	synonymous	Exon 5 of 9	NP_955366.1
	THRA	NM_001190919.2		c.351C>T	p.Ala117Ala	synonymous	Exon 5 of 10	NP_001177848.1
	THRA	NM_003250.6		c.351C>T	p.Ala117Ala	synonymous	Exon 5 of 10	NP_003241.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THRA	ENST00000450525.7	TSL:1 MANE Select	c.351C>T	p.Ala117Ala	synonymous	Exon 5 of 9	ENSP00000395641.3
	THRA	ENST00000264637.8	TSL:1	c.351C>T	p.Ala117Ala	synonymous	Exon 5 of 10	ENSP00000264637.4
	THRA	ENST00000584985.5	TSL:1	c.351C>T	p.Ala117Ala	synonymous	Exon 5 of 10	ENSP00000463466.1

Frequencies

GnomAD3 genomes AF: 0.0394 AC: 6002 AN: 152148 Hom.: 147 Cov.: 32

Gnomad AFR AF: 0.0381

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0240

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.00539

Gnomad SAS AF: 0.0254

Gnomad FIN AF: 0.0439

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0482

Gnomad OTH AF: 0.0363

GnomAD2 exomes AF: 0.0365 AC: 9131 AN: 250440 AF XY: 0.0361

Gnomad AFR exome AF: 0.0396

Gnomad AMR exome AF: 0.0182

Gnomad ASJ exome AF: 0.0181

Gnomad EAS exome AF: 0.00802

Gnomad FIN exome AF: 0.0435

Gnomad NFE exome AF: 0.0468

Gnomad OTH exome AF: 0.0371

GnomAD4 exome AF: 0.0452 AC: 66057 AN: 1460956 Hom.: 1718 Cov.: 30 AF XY: 0.0443 AC XY: 32173 AN XY: 726788

African (AFR) AF: 0.0411 AC: 1375 AN: 33446

American (AMR) AF: 0.0194 AC: 866 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.0177 AC: 462 AN: 26092

East Asian (EAS) AF: 0.00358 AC: 142 AN: 39642

South Asian (SAS) AF: 0.0324 AC: 2788 AN: 86142

European-Finnish (FIN) AF: 0.0463 AC: 2475 AN: 53400

Middle Eastern (MID) AF: 0.0116 AC: 67 AN: 5762

European-Non Finnish (NFE) AF: 0.0498 AC: 55372 AN: 1111474

Other (OTH) AF: 0.0416 AC: 2510 AN: 60354

GnomAD4 genome AF: 0.0395 AC: 6022 AN: 152266 Hom.: 151 Cov.: 32 AF XY: 0.0376 AC XY: 2796 AN XY: 74424

African (AFR) AF: 0.0385 AC: 1599 AN: 41562

American (AMR) AF: 0.0240 AC: 367 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 50 AN: 3472

East Asian (EAS) AF: 0.00541 AC: 28 AN: 5178

South Asian (SAS) AF: 0.0255 AC: 123 AN: 4832

European-Finnish (FIN) AF: 0.0439 AC: 466 AN: 10606

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0482 AC: 3280 AN: 68004

Other (OTH) AF: 0.0360 AC: 76 AN: 2114

Alfa AF: 0.0434 Hom.: 169

Bravo AF: 0.0383

Asia WGS AF: 0.0420 AC: 145 AN: 3478

EpiCase AF: 0.0415

EpiControl AF: 0.0412

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	10
DANN	Benign	0.72
PhyloP100		-5.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2230701; hg19: chr17-38240216; COSMIC: COSV52843038; COSMIC: COSV52843038;