NM_000369.5:c.615-290G>A

Variant names:

• chr14-81108085-G-A
• rs12885526
• NM_000369.5:c.615-290G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000369.5(TSHR):​c.615-290G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.625 in 151,804 control chromosomes in the GnomAD database, including 30,080 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.62 (30080 hom., cov: 31)
• Consequence: TSHR NM_000369.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.416
• Publications: 7 publications found

Genes affected

TSHR (HGNC:12373): (thyroid stimulating hormone receptor) The protein encoded by this gene is a membrane protein and a major controller of thyroid cell metabolism. The encoded protein is a receptor for thyrothropin and thyrostimulin, and its activity is mediated by adenylate cyclase. Defects in this gene are a cause of several types of hyperthyroidism. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

TSHR Gene-Disease associations (from GenCC):

• familial gestational hyperthyroidism

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• hypothyroidism due to TSH receptor mutations

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• familial hyperthyroidism due to mutations in TSH receptor

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• athyreosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• thyroid hypoplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TSHR-AS1 (HGNC:58172):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.707 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000369.5. 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
	TSHR	NM_000369.5	MANE Select	c.615-290G>A		intron	N/A	NP_000360.2	P16473-1
	TSHR	NM_001142626.3		c.615-290G>A		intron	N/A	NP_001136098.1	P16473-3
	TSHR	NM_001018036.3		c.615-290G>A		intron	N/A	NP_001018046.1	P16473-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSHR	ENST00000298171.7	TSL:1 MANE Select	c.615-290G>A		intron	N/A	ENSP00000298171.2	P16473-1
	TSHR	ENST00000554435.1	TSL:1	c.615-290G>A		intron	N/A	ENSP00000450549.1	P16473-3
	TSHR	ENST00000342443.10	TSL:1	c.615-290G>A		intron	N/A	ENSP00000340113.6	P16473-2

Frequencies

GnomAD3 genomes AF: 0.625 AC: 94814 AN: 151688 Hom.: 30070 Cov.: 31

Gnomad AFR AF: 0.593

Gnomad AMI AF: 0.431

Gnomad AMR AF: 0.618

Gnomad ASJ AF: 0.748

Gnomad EAS AF: 0.353

Gnomad SAS AF: 0.725

Gnomad FIN AF: 0.672

Gnomad MID AF: 0.715

Gnomad NFE AF: 0.648

Gnomad OTH AF: 0.648

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.625 AC: 94873 AN: 151804 Hom.: 30080 Cov.: 31 AF XY: 0.623 AC XY: 46237 AN XY: 74178

African (AFR) AF: 0.593 AC: 24506 AN: 41360

American (AMR) AF: 0.618 AC: 9414 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.748 AC: 2593 AN: 3468

East Asian (EAS) AF: 0.353 AC: 1823 AN: 5160

South Asian (SAS) AF: 0.727 AC: 3504 AN: 4822

European-Finnish (FIN) AF: 0.672 AC: 7063 AN: 10514

Middle Eastern (MID) AF: 0.714 AC: 210 AN: 294

European-Non Finnish (NFE) AF: 0.648 AC: 44008 AN: 67930

Other (OTH) AF: 0.646 AC: 1361 AN: 2108

Alfa AF: 0.632 Hom.: 3941

Bravo AF: 0.617

Asia WGS AF: 0.594 AC: 2063 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.56
DANN	Benign	0.59
PhyloP100		-0.42
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs12885526; hg19: chr14-81574429; COSMIC: COSV53332933; COSMIC: COSV53332933;