17-40083830-C-G

Variant names:

• chr17-40083830-C-G
• rs200727359
• NM_199334.5:c.223-5C>G

Variant summary

Our verdict is Benign. The variant received -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, 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, intron
• Scores: Splicing: ADA: 0.009263
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.265
• 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: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 723441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 69 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.223-5C>G		splice_region intron	N/A	NP_955366.1	Q6FH41
	THRA	NM_001190919.2		c.223-5C>G		splice_region intron	N/A	NP_001177848.1	P10827-1
	THRA	NM_003250.6		c.223-5C>G		splice_region intron	N/A	NP_003241.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THRA	ENST00000450525.7	TSL:1 MANE Select	c.223-5C>G		splice_region intron	N/A	ENSP00000395641.3	P10827-2
	THRA	ENST00000264637.8	TSL:1	c.223-5C>G		splice_region intron	N/A	ENSP00000264637.4	P10827-1
	THRA	ENST00000584985.5	TSL:1	c.223-5C>G		splice_region intron	N/A	ENSP00000463466.1	P10827-3

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

GnomAD2 exomes AF: 0.00125 AC: 297 AN: 237878 AF XY: 0.00168

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33106

American (AMR) AF: 0.00131 AC: 57 AN: 43448

Ashkenazi Jewish (ASJ) AF: 0.000518 AC: 13 AN: 25098

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39244

South Asian (SAS) AF: 0.00647 AC: 541 AN: 83612

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52850

Middle Eastern (MID) AF: 0.00351 AC: 20 AN: 5702

European-Non Finnish (NFE) AF: 0.000264 AC: 291 AN: 1103358

Other (OTH) AF: 0.000853 AC: 51 AN: 59782

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

African (AFR) AF: 0.0000963 AC: 4 AN: 41558

American (AMR) AF: 0.000850 AC: 13 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

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

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68030

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000608 Hom.: 0

Bravo AF: 0.000336

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	7.9
DANN	Benign	0.67
PhyloP100		0.27
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs200727359; hg19: chr17-38240083;