chr14-81087389-G-A

Variant names:

• chr14-81087389-G-A
• rs2284734
• NM_000369.5:c.318-565G>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.318-565G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.558 in 157,814 control chromosomes in the GnomAD database, including 27,128 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 0.55 (25882 hom., cov: 32)
  • Exomes 𝑓: 0.65 (1246 hom.)
• Consequence: TSHR NM_000369.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.113
• Publications: 8 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: G2P, Orphanet
• hypothyroidism due to TSH receptor mutations

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• 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=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.675 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSHR	NM_000369.5	c.318-565G>A		intron_variant	Intron 3 of 9	ENST00000298171.7	NP_000360.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSHR	ENST00000298171.7	c.318-565G>A		intron_variant	Intron 3 of 9	1	NM_000369.5	ENSP00000298171.2

Frequencies

GnomAD3 genomes AF: 0.555 AC: 84242 AN: 151914 Hom.: 25886 Cov.: 32

Gnomad AFR AF: 0.276

Gnomad AMI AF: 0.485

Gnomad AMR AF: 0.588

Gnomad ASJ AF: 0.701

Gnomad EAS AF: 0.450

Gnomad SAS AF: 0.656

Gnomad FIN AF: 0.737

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.681

Gnomad OTH AF: 0.596

GnomAD4 exome AF: 0.649 AC: 3754 AN: 5782 Hom.: 1246 AF XY: 0.648 AC XY: 1936 AN XY: 2988

African (AFR) AF: 0.200 AC: 4 AN: 20

American (AMR) AF: 0.631 AC: 793 AN: 1256

Ashkenazi Jewish (ASJ) AF: 0.778 AC: 14 AN: 18

East Asian (EAS) AF: 0.428 AC: 83 AN: 194

South Asian (SAS) AF: 0.669 AC: 407 AN: 608

European-Finnish (FIN) AF: 0.783 AC: 47 AN: 60

Middle Eastern (MID) AF: 0.500 AC: 2 AN: 4

European-Non Finnish (NFE) AF: 0.667 AC: 2266 AN: 3398

Other (OTH) AF: 0.616 AC: 138 AN: 224

GnomAD4 genome AF: 0.554 AC: 84248 AN: 152032 Hom.: 25882 Cov.: 32 AF XY: 0.556 AC XY: 41291 AN XY: 74330

African (AFR) AF: 0.275 AC: 11390 AN: 41432

American (AMR) AF: 0.588 AC: 8974 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.701 AC: 2432 AN: 3470

East Asian (EAS) AF: 0.450 AC: 2326 AN: 5170

South Asian (SAS) AF: 0.658 AC: 3167 AN: 4816

European-Finnish (FIN) AF: 0.737 AC: 7794 AN: 10580

Middle Eastern (MID) AF: 0.673 AC: 198 AN: 294

European-Non Finnish (NFE) AF: 0.681 AC: 46273 AN: 67982

Other (OTH) AF: 0.593 AC: 1254 AN: 2114

Alfa AF: 0.654 Hom.: 64671

Bravo AF: 0.530

Asia WGS AF: 0.505 AC: 1756 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.5
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: rs2284734; hg19: chr14-81553733; COSMIC: COSV107314909;