NM_000369.5:c.170+48461C>A

Variant names:

• chr14-81004311-C-A
• rs917986
• NM_000369.5:c.170+48461C>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.170+48461C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.624 in 152,060 control chromosomes in the GnomAD database, including 32,296 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 (32296 hom., cov: 32)
• Consequence: TSHR NM_000369.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00600
• Publications: 14 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.761 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSHR	NM_000369.5	c.170+48461C>A		intron_variant	Intron 1 of 9	ENST00000298171.7	NP_000360.2
TSHR	NM_001142626.3	c.170+48461C>A		intron_variant	Intron 1 of 8		NP_001136098.1
TSHR	NM_001018036.3	c.170+48461C>A		intron_variant	Intron 1 of 8		NP_001018046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSHR	ENST00000298171.7	c.170+48461C>A		intron_variant	Intron 1 of 9	1	NM_000369.5	ENSP00000298171.2

Frequencies

GnomAD3 genomes AF: 0.625 AC: 94890 AN: 151942 Hom.: 32287 Cov.: 32

Gnomad AFR AF: 0.329

Gnomad AMI AF: 0.771

Gnomad AMR AF: 0.685

Gnomad ASJ AF: 0.620

Gnomad EAS AF: 0.611

Gnomad SAS AF: 0.783

Gnomad FIN AF: 0.777

Gnomad MID AF: 0.598

Gnomad NFE AF: 0.754

Gnomad OTH AF: 0.647

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

GnomAD4 genome AF: 0.624 AC: 94929 AN: 152060 Hom.: 32296 Cov.: 32 AF XY: 0.629 AC XY: 46775 AN XY: 74326

African (AFR) AF: 0.329 AC: 13637 AN: 41424

American (AMR) AF: 0.685 AC: 10463 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.620 AC: 2150 AN: 3466

East Asian (EAS) AF: 0.611 AC: 3150 AN: 5156

South Asian (SAS) AF: 0.782 AC: 3772 AN: 4824

European-Finnish (FIN) AF: 0.777 AC: 8222 AN: 10588

Middle Eastern (MID) AF: 0.605 AC: 178 AN: 294

European-Non Finnish (NFE) AF: 0.754 AC: 51301 AN: 68002

Other (OTH) AF: 0.641 AC: 1353 AN: 2112

Alfa AF: 0.708 Hom.: 173579

Bravo AF: 0.602

Asia WGS AF: 0.652 AC: 2272 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.2
DANN	Benign	0.62
PhyloP100		0.0060
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: rs917986; hg19: chr14-81470655;