chr14-81087993-T-A

Variant names:

• chr14-81087993-T-A
• rs144084915
• NM_000369.5:c.357T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_000369.5(TSHR):​c.357T>A​(p.Pro119Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00254 in 1,613,932 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (11 hom.)
• Consequence: TSHR NM_000369.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 0.376
• Publications: 2 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=-0.45).
• BP6: Variant 14-81087993-T-A is Benign according to our data. Variant chr14-81087993-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 314692.
• BP7: Synonymous conserved (PhyloP=0.376 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00263 (3850/1461628) while in subpopulation NFE AF = 0.00306 (3401/1111804). AF 95% confidence interval is 0.00297. There are 11 homozygotes in GnomAdExome4. There are 1958 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 11 AD,AR gene

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.357T>A	p.Pro119Pro	synonymous	Exon 4 of 10	NP_000360.2	P16473-1
	TSHR	NM_001142626.3		c.357T>A	p.Pro119Pro	synonymous	Exon 4 of 9	NP_001136098.1	P16473-3
	TSHR	NM_001018036.3		c.357T>A	p.Pro119Pro	synonymous	Exon 4 of 9	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.357T>A	p.Pro119Pro	synonymous	Exon 4 of 10	ENSP00000298171.2	P16473-1
	TSHR	ENST00000554435.1	TSL:1	c.357T>A	p.Pro119Pro	synonymous	Exon 4 of 9	ENSP00000450549.1	P16473-3
	TSHR	ENST00000342443.10	TSL:1	c.357T>A	p.Pro119Pro	synonymous	Exon 4 of 9	ENSP00000340113.6	P16473-2

Frequencies

GnomAD3 genomes AF: 0.00169 AC: 257 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00269

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00175 AC: 440 AN: 251418 AF XY: 0.00191

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00270

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00263 AC: 3850 AN: 1461628 Hom.: 11 Cov.: 30 AF XY: 0.00269 AC XY: 1958 AN XY: 727140

African (AFR) AF: 0.000627 AC: 21 AN: 33468

American (AMR) AF: 0.00121 AC: 54 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.00239 AC: 206 AN: 86250

European-Finnish (FIN) AF: 0.000225 AC: 12 AN: 53416

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.00306 AC: 3401 AN: 1111804

Other (OTH) AF: 0.00252 AC: 152 AN: 60374

GnomAD4 genome AF: 0.00169 AC: 257 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.00167 AC XY: 124 AN XY: 74470

African (AFR) AF: 0.000505 AC: 21 AN: 41562

American (AMR) AF: 0.00255 AC: 39 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4826

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00269 AC: 183 AN: 68016

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00213 Hom.: 0

Bravo AF: 0.00201

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00382

EpiControl AF: 0.00290

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not specified (3)
-	-	2	not provided (2)
-	-	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	-0.45
CADD	Benign	5.5
DANN	Benign	0.74
PhyloP100		0.38
Mutation Taster		=100/0	polymorphism

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: rs144084915; hg19: chr14-81554337;