rs61743974

Variant names:

• chr14-81144290-C-G
• rs61743974
• NM_000369.5:c.2232C>G

Your query was ambiguous. Multiple possible variants found:

• chr14-81144290-C-G
• chr14-81144290-C-T

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.2232C>G​(p.Asn744Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00307 in 1,614,140 control chromosomes in the GnomAD database, including 164 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 0.016 (79 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (85 hom.)
• Consequence: TSHR NM_000369.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 0.0280
• Publications: 3 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=0.0018980801).
• BP6: Variant 14-81144290-C-G is Benign according to our data. Variant chr14-81144290-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 135396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0533 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.2232C>G	p.Asn744Lys	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.2232C>G	p.Asn744Lys	missense	Exon 10 of 10	ENSP00000298171.2	P16473-1
	TSHR	ENST00000541158.6	TSL:5	c.2232C>G	p.Asn744Lys	missense	Exon 11 of 11	ENSP00000441235.2	P16473-1
	TSHR	ENST00000637447.1	TSL:5	n.1134C>G		non_coding_transcript_exon	Exon 1 of 2	ENSP00000490136.1	A0A1B0GUJ5

Frequencies

GnomAD3 genomes AF: 0.0159 AC: 2421 AN: 152152 Hom.: 78 Cov.: 32

Gnomad AFR AF: 0.0552

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00556

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.00416 AC: 1045 AN: 251390 AF XY: 0.00296

Gnomad AFR exome AF: 0.0565

Gnomad AMR exome AF: 0.00260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00173 AC: 2528 AN: 1461870 Hom.: 85 Cov.: 34 AF XY: 0.00146 AC XY: 1064 AN XY: 727236

African (AFR) AF: 0.0629 AC: 2107 AN: 33480

American (AMR) AF: 0.00304 AC: 136 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5768

European-Non Finnish (NFE) AF: 0.0000477 AC: 53 AN: 1111998

Other (OTH) AF: 0.00344 AC: 208 AN: 60394

GnomAD4 genome AF: 0.0159 AC: 2426 AN: 152270 Hom.: 79 Cov.: 32 AF XY: 0.0160 AC XY: 1195 AN XY: 74462

African (AFR) AF: 0.0552 AC: 2292 AN: 41542

American (AMR) AF: 0.00555 AC: 85 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68016

Other (OTH) AF: 0.0151 AC: 32 AN: 2114

Alfa AF: 0.00246 Hom.: 2

Bravo AF: 0.0184

ESP6500AA AF: 0.0545 AC: 240

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00500 AC: 607

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Familial hyperthyroidism due to mutations in TSH receptor (1)
-	-	1	Hypothyroidism due to TSH receptor mutations (1)
-	-	1	TSHR-related disorder (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	3.5
DANN	Benign	0.94
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.028
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.078
Sift	Benign	0.21	T
Sift4G	Benign	0.41	T
Vest4		0.063
MutPred		0.46		Gain of catalytic residue at L747 (P = 5e-04)
MVP		0.77
MPC		0.18
ClinPred		0.0017	T
GERP RS		1.1
gMVP		0.36
Mutation Taster		=99/1	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: rs61743974; hg19: chr14-81610634;