rs61747482

Variant names:

• chr14-80955786-G-C
• rs61747482
• NM_000369.5:c.106G>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000369.5(TSHR):​c.106G>C​(p.Asp36His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00697 in 1,614,204 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0072 (43 hom.)
• Consequence: TSHR NM_000369.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 1.11
• Publications: 34 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]

CEP128 (HGNC:20359): (centrosomal protein 128) Involved in protein localization. Located in centriole and spindle pole. Part of centriolar subdistal appendage. [provided by Alliance of Genome Resources, Apr 2022]

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=0.00600639).
• BP6: Variant 14-80955786-G-C is Benign according to our data. Variant chr14-80955786-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 6430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00484 (738/152330) while in subpopulation NFE AF = 0.00866 (589/68028). AF 95% confidence interval is 0.00808. There are 4 homozygotes in GnomAd4. There are 354 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.106G>C	p.Asp36His	missense	Exon 1 of 10	NP_000360.2	P16473-1
	TSHR	NM_001142626.3		c.106G>C	p.Asp36His	missense	Exon 1 of 9	NP_001136098.1	P16473-3
	TSHR	NM_001018036.3		c.106G>C	p.Asp36His	missense	Exon 1 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.106G>C	p.Asp36His	missense	Exon 1 of 10	ENSP00000298171.2	P16473-1
	TSHR	ENST00000554435.1	TSL:1	c.106G>C	p.Asp36His	missense	Exon 1 of 9	ENSP00000450549.1	P16473-3
	TSHR	ENST00000342443.10	TSL:1	c.106G>C	p.Asp36His	missense	Exon 1 of 9	ENSP00000340113.6	P16473-2

Frequencies

GnomAD3 genomes AF: 0.00485 AC: 738 AN: 152212 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00471

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00866

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00517 AC: 1294 AN: 250062 AF XY: 0.00532

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00476

Gnomad NFE exome AF: 0.00926

Gnomad OTH exome AF: 0.00472

GnomAD4 exome AF: 0.00719 AC: 10511 AN: 1461874 Hom.: 43 Cov.: 31 AF XY: 0.00700 AC XY: 5091 AN XY: 727234

African (AFR) AF: 0.00102 AC: 34 AN: 33478

American (AMR) AF: 0.000604 AC: 27 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00302 AC: 79 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00189 AC: 163 AN: 86258

European-Finnish (FIN) AF: 0.00498 AC: 266 AN: 53402

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.00867 AC: 9646 AN: 1112012

Other (OTH) AF: 0.00479 AC: 289 AN: 60396

GnomAD4 genome AF: 0.00484 AC: 738 AN: 152330 Hom.: 4 Cov.: 33 AF XY: 0.00475 AC XY: 354 AN XY: 74482

African (AFR) AF: 0.00111 AC: 46 AN: 41582

American (AMR) AF: 0.00144 AC: 22 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4826

European-Finnish (FIN) AF: 0.00471 AC: 50 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00866 AC: 589 AN: 68028

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00702 Hom.: 4

Bravo AF: 0.00457

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.00756 AC: 65

ExAC AF: 0.00601 AC: 730

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00649

EpiControl AF: 0.00717

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (3)
-	-	1	Familial hyperthyroidism due to mutations in TSH receptor (1)
-	-	1	Graves disease, susceptibility to, 1 (1)
-	-	1	Hypothyroidism due to TSH receptor mutations (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	0.073
Eigen_PC	Benign	0.066
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.97	L
PhyloP100		1.1
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.28
Sift	Benign	0.56	T
Sift4G	Benign	0.51	T
Polyphen		1.0	D
Vest4		0.20
MVP		0.97
MPC		0.18
ClinPred		0.022	T
GERP RS		2.3
PromoterAI		-0.037	Neutral
gMVP		0.66
Mutation Taster		=91/9	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: rs61747482; hg19: chr14-81422130; COSMIC: COSV99035859; COSMIC: COSV99035859;