chr14-81056784-T-C

Variant names:

• chr14-81056784-T-C
• rs17111394
• NM_000369.5:c.171-5364T>C

Variant summary

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

The NM_000369.5(TSHR):​c.171-5364T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 152,208 control chromosomes in the GnomAD database, including 1,591 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 0.13 (1591 hom., cov: 32)
• Consequence: TSHR NM_000369.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.587
• Publications: 11 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

ENSG00000284959 (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 (NFE) allele frequency at 95% confidence interval = 0.181 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSHR	NM_000369.5	MANE Select	c.171-5364T>C		intron	N/A	NP_000360.2
	TSHR	NM_001142626.3		c.171-5364T>C		intron	N/A	NP_001136098.1
	TSHR	NM_001018036.3		c.171-5364T>C		intron	N/A	NP_001018046.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSHR	ENST00000298171.7	TSL:1 MANE Select	c.171-5364T>C		intron	N/A	ENSP00000298171.2
	TSHR	ENST00000554435.1	TSL:1	c.171-5364T>C		intron	N/A	ENSP00000450549.1
	TSHR	ENST00000342443.10	TSL:1	c.171-5364T>C		intron	N/A	ENSP00000340113.6

Frequencies

GnomAD3 genomes AF: 0.132 AC: 20051 AN: 152090 Hom.: 1593 Cov.: 32

Gnomad AFR AF: 0.0525

Gnomad AMI AF: 0.251

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.160

Gnomad SAS AF: 0.0895

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.121

Gnomad NFE AF: 0.184

Gnomad OTH AF: 0.124

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

GnomAD4 genome AF: 0.132 AC: 20057 AN: 152208 Hom.: 1591 Cov.: 32 AF XY: 0.129 AC XY: 9589 AN XY: 74394

African (AFR) AF: 0.0526 AC: 2186 AN: 41574

American (AMR) AF: 0.111 AC: 1702 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 559 AN: 3470

East Asian (EAS) AF: 0.160 AC: 828 AN: 5162

South Asian (SAS) AF: 0.0896 AC: 432 AN: 4822

European-Finnish (FIN) AF: 0.124 AC: 1318 AN: 10602

Middle Eastern (MID) AF: 0.130 AC: 38 AN: 292

European-Non Finnish (NFE) AF: 0.184 AC: 12509 AN: 67986

Other (OTH) AF: 0.122 AC: 257 AN: 2110

Alfa AF: 0.161 Hom.: 4716

Bravo AF: 0.129

Asia WGS AF: 0.105 AC: 367 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.2
DANN	Benign	0.70
PhyloP100		0.59
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: rs17111394; hg19: chr14-81523128;