14-81144239-G-C

Variant names:

• chr14-81144239-G-C
• rs1991517
• NM_000369.5:c.2181G>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000369.5(TSHR):​c.2181G>C​(p.Glu727Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.911 in 1,613,402 control chromosomes in the GnomAD database, including 669,969 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.91 (62803 hom., cov: 31)
  • Exomes 𝑓: 0.91 (607166 hom.)
• Consequence: TSHR NM_000369.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: -0.107
• Publications: 108 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 -19 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 43 curated pathogenic missense variants (we use a threshold of 10). The gene has 11 curated benign missense variants. Gene score misZ: 0.33445 (below the threshold of 3.09). Trascript score misZ: 1.3127 (below the threshold of 3.09). GenCC associations: The gene is linked to hypothyroidism due to TSH receptor mutations, athyreosis, familial hyperthyroidism due to mutations in TSH receptor, familial gestational hyperthyroidism, thyroid hypoplasia.
• BP4: Computational evidence support a benign effect (MetaRNN=9.633978E-7).
• BP6: Variant 14-81144239-G-C is Benign according to our data. Variant chr14-81144239-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 135400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.932 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.2181G>C	p.Glu727Asp	missense	Exon 10 of 10	NP_000360.2	P16473-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSHR	ENST00000298171.7	TSL:1 MANE Select	c.2181G>C	p.Glu727Asp	missense	Exon 10 of 10	ENSP00000298171.2	P16473-1
	TSHR	ENST00000541158.6	TSL:5	c.2181G>C	p.Glu727Asp	missense	Exon 11 of 11	ENSP00000441235.2	P16473-1
	TSHR	ENST00000637447.1	TSL:5	n.1083G>C		non_coding_transcript_exon	Exon 1 of 2	ENSP00000490136.1	A0A1B0GUJ5

Frequencies

GnomAD3 genomes AF: 0.907 AC: 137998 AN: 152072 Hom.: 62747 Cov.: 31

Gnomad AFR AF: 0.940

Gnomad AMI AF: 0.865

Gnomad AMR AF: 0.862

Gnomad ASJ AF: 0.901

Gnomad EAS AF: 0.838

Gnomad SAS AF: 0.913

Gnomad FIN AF: 0.843

Gnomad MID AF: 0.934

Gnomad NFE AF: 0.913

Gnomad OTH AF: 0.916

GnomAD2 exomes AF: 0.896 AC: 224904 AN: 251048 AF XY: 0.898

Gnomad AFR exome AF: 0.938

Gnomad AMR exome AF: 0.870

Gnomad ASJ exome AF: 0.907

Gnomad EAS exome AF: 0.821

Gnomad FIN exome AF: 0.847

Gnomad NFE exome AF: 0.913

Gnomad OTH exome AF: 0.898

GnomAD4 exome AF: 0.911 AC: 1331625 AN: 1461212 Hom.: 607166 Cov.: 73 AF XY: 0.911 AC XY: 662347 AN XY: 726864

African (AFR) AF: 0.936 AC: 31291 AN: 33430

American (AMR) AF: 0.869 AC: 38817 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.906 AC: 23631 AN: 26086

East Asian (EAS) AF: 0.848 AC: 33670 AN: 39686

South Asian (SAS) AF: 0.913 AC: 78708 AN: 86246

European-Finnish (FIN) AF: 0.848 AC: 45298 AN: 53410

Middle Eastern (MID) AF: 0.934 AC: 5385 AN: 5768

European-Non Finnish (NFE) AF: 0.918 AC: 1019920 AN: 1111560

Other (OTH) AF: 0.910 AC: 54905 AN: 60364

GnomAD4 genome AF: 0.907 AC: 138109 AN: 152190 Hom.: 62803 Cov.: 31 AF XY: 0.903 AC XY: 67137 AN XY: 74374

African (AFR) AF: 0.940 AC: 39044 AN: 41526

American (AMR) AF: 0.862 AC: 13175 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.901 AC: 3128 AN: 3472

East Asian (EAS) AF: 0.838 AC: 4333 AN: 5170

South Asian (SAS) AF: 0.912 AC: 4389 AN: 4810

European-Finnish (FIN) AF: 0.843 AC: 8921 AN: 10580

Middle Eastern (MID) AF: 0.932 AC: 274 AN: 294

European-Non Finnish (NFE) AF: 0.913 AC: 62120 AN: 68024

Other (OTH) AF: 0.918 AC: 1936 AN: 2110

Alfa AF: 0.910 Hom.: 20441

Bravo AF: 0.910

TwinsUK AF: 0.917 AC: 3400

ALSPAC AF: 0.920 AC: 3545

ESP6500AA AF: 0.943 AC: 4154

ESP6500EA AF: 0.913 AC: 7855

ExAC AF: 0.900 AC: 109299

Asia WGS AF: 0.897 AC: 3118 AN: 3478

EpiCase AF: 0.921

EpiControl AF: 0.917

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (5)
-	-	3	not provided (3)
-	-	2	Familial hyperthyroidism due to mutations in TSH receptor (2)
-	-	2	Hypothyroidism due to TSH receptor mutations (2)
-	-	1	Familial gestational hyperthyroidism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	2.1
DANN	Benign	0.45
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0092	N
LIST_S2	Benign	0.11	T
MetaRNN	Benign	9.6e-7	T
MetaSVM	Benign	-0.98	T
PhyloP100		-0.11
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.073
Sift	Benign	1.0	T
Sift4G	Benign	0.76	T
Vest4		0.012
MutPred		0.32		Gain of catalytic residue at V724 (P = 0.0078)
MPC		0.14
ClinPred		0.0011	T
GERP RS		2.1
gMVP		0.32
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: rs1991517; hg19: chr14-81610583; COSMIC: COSV107314885; COSMIC: COSV107314885;