rs2241119

Variant names:

• chr14-81092621-A-G
• rs2241119
• NM_000369.5:c.545+13A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000369.5(TSHR):​c.545+13A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 1,610,764 control chromosomes in the GnomAD database, including 28,193 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (7444 hom., cov: 32)
  • Exomes 𝑓: 0.15 (20749 hom.)
• Consequence: TSHR NM_000369.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.113
• Publications: 23 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 14-81092621-A-G is Benign according to our data. Variant chr14-81092621-A-G is described in ClinVar as Benign. ClinVar VariationId is 255952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.532 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.545+13A>G		intron	N/A	NP_000360.2	P16473-1
	TSHR	NM_001142626.3		c.545+13A>G		intron	N/A	NP_001136098.1	P16473-3
	TSHR	NM_001018036.3		c.545+13A>G		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.545+13A>G		intron	N/A	ENSP00000298171.2	P16473-1
	TSHR	ENST00000554435.1	TSL:1	c.545+13A>G		intron	N/A	ENSP00000450549.1	P16473-3
	TSHR	ENST00000342443.10	TSL:1	c.545+13A>G		intron	N/A	ENSP00000340113.6	P16473-2

Frequencies

GnomAD3 genomes AF: 0.256 AC: 38857 AN: 151896 Hom.: 7414 Cov.: 32

Gnomad AFR AF: 0.537

Gnomad AMI AF: 0.231

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.328

Gnomad SAS AF: 0.170

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.195

GnomAD2 exomes AF: 0.180 AC: 45239 AN: 251226 AF XY: 0.173

Gnomad AFR exome AF: 0.548

Gnomad AMR exome AF: 0.123

Gnomad ASJ exome AF: 0.145

Gnomad EAS exome AF: 0.337

Gnomad FIN exome AF: 0.151

Gnomad NFE exome AF: 0.135

Gnomad OTH exome AF: 0.151

GnomAD4 exome AF: 0.150 AC: 218875 AN: 1458752 Hom.: 20749 Cov.: 30 AF XY: 0.149 AC XY: 108322 AN XY: 725930

African (AFR) AF: 0.558 AC: 18618 AN: 33392

American (AMR) AF: 0.127 AC: 5700 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 3750 AN: 26118

East Asian (EAS) AF: 0.324 AC: 12853 AN: 39662

South Asian (SAS) AF: 0.162 AC: 13996 AN: 86194

European-Finnish (FIN) AF: 0.149 AC: 7925 AN: 53328

Middle Eastern (MID) AF: 0.170 AC: 977 AN: 5764

European-Non Finnish (NFE) AF: 0.131 AC: 145016 AN: 1109316

Other (OTH) AF: 0.167 AC: 10040 AN: 60270

GnomAD4 genome AF: 0.256 AC: 38940 AN: 152012 Hom.: 7444 Cov.: 32 AF XY: 0.254 AC XY: 18903 AN XY: 74322

African (AFR) AF: 0.538 AC: 22272 AN: 41408

American (AMR) AF: 0.150 AC: 2287 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 528 AN: 3468

East Asian (EAS) AF: 0.328 AC: 1689 AN: 5154

South Asian (SAS) AF: 0.169 AC: 815 AN: 4828

European-Finnish (FIN) AF: 0.157 AC: 1657 AN: 10586

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.133 AC: 9029 AN: 67982

Other (OTH) AF: 0.195 AC: 412 AN: 2112

Alfa AF: 0.178 Hom.: 10681

Bravo AF: 0.271

Asia WGS AF: 0.254 AC: 884 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Familial hyperthyroidism due to mutations in TSH receptor (1)
-	-	1	Hypothyroidism due to TSH receptor mutations (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	10
DANN	Benign	0.61
PhyloP100		0.11
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: rs2241119; hg19: chr14-81558965; COSMIC: COSV53318237; COSMIC: COSV53318237;