rs41283431

Variant names:

• chr17-40088256-C-T
• rs41283431
• NM_199334.5:c.738C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_199334.5(THRA):​c.738C>T​(p.Asp246Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0042 in 1,593,706 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0043 (16 hom.)
• Consequence: THRA NM_199334.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.13
• Publications: 1 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: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 17-40088256-C-T is Benign according to our data. Variant chr17-40088256-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.13 with no splicing effect.
• BS2: High AC in GnomAd4 at 486 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THRA	NM_199334.5	MANE Select	c.738C>T	p.Asp246Asp	synonymous	Exon 8 of 9	NP_955366.1	Q6FH41
	THRA	NM_001190919.2		c.738C>T	p.Asp246Asp	synonymous	Exon 8 of 10	NP_001177848.1	P10827-1
	THRA	NM_003250.6		c.738C>T	p.Asp246Asp	synonymous	Exon 8 of 10	NP_003241.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THRA	ENST00000450525.7	TSL:1 MANE Select	c.738C>T	p.Asp246Asp	synonymous	Exon 8 of 9	ENSP00000395641.3	P10827-2
	THRA	ENST00000264637.8	TSL:1	c.738C>T	p.Asp246Asp	synonymous	Exon 8 of 10	ENSP00000264637.4	P10827-1
	THRA	ENST00000584985.5	TSL:1	c.738C>T	p.Asp246Asp	synonymous	Exon 8 of 10	ENSP00000463466.1	P10827-3

Frequencies

GnomAD3 genomes AF: 0.00320 AC: 487 AN: 152220 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00753

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00451

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00351 AC: 832 AN: 236908 AF XY: 0.00352

Gnomad AFR exome AF: 0.000371

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.00143

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00750

Gnomad NFE exome AF: 0.00523

Gnomad OTH exome AF: 0.00452

GnomAD4 exome AF: 0.00430 AC: 6203 AN: 1441368 Hom.: 16 Cov.: 32 AF XY: 0.00423 AC XY: 3025 AN XY: 714408

African (AFR) AF: 0.000572 AC: 19 AN: 33202

American (AMR) AF: 0.00232 AC: 101 AN: 43506

Ashkenazi Jewish (ASJ) AF: 0.00110 AC: 27 AN: 24530

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39476

South Asian (SAS) AF: 0.000337 AC: 28 AN: 83060

European-Finnish (FIN) AF: 0.00711 AC: 374 AN: 52572

Middle Eastern (MID) AF: 0.0139 AC: 79 AN: 5680

European-Non Finnish (NFE) AF: 0.00485 AC: 5330 AN: 1099828

Other (OTH) AF: 0.00410 AC: 244 AN: 59514

GnomAD4 genome AF: 0.00319 AC: 486 AN: 152338 Hom.: 1 Cov.: 31 AF XY: 0.00293 AC XY: 218 AN XY: 74500

African (AFR) AF: 0.000577 AC: 24 AN: 41582

American (AMR) AF: 0.00385 AC: 59 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00753 AC: 80 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00451 AC: 307 AN: 68032

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00318 Hom.: 0

Bravo AF: 0.00284

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	13
DANN	Benign	0.89
PhyloP100		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs41283431; hg19: chr17-38244509;