rs5658

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_007117.5(TRH):c.22C>G(p.Leu8Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 1,608,952 control chromosomes in the GnomAD database, including 13,151 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 2354 hom., cov: 33)

Exomes 𝑓: 0.10 ( 10797 hom. )

Consequence

TRH
NM_007117.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.87

Publications

24 publications found

Variant links:

Genes affected

TRH (HGNC:12298): (thyrotropin releasing hormone) This gene encodes a member of the thyrotropin-releasing hormone family. Cleavage of the encoded proprotein releases mature thyrotropin-releasing hormone, which is a tripeptide hypothalamic regulatory hormone. The human proprotein contains six thyrotropin-releasing hormone tripeptides. Thyrotropin-releasing hormone is involved in the regulation and release of thyroid-stimulating hormone, as well as prolactin. Deficiency of this hormone has been associated with hypothalamic hypothyroidism. [provided by RefSeq, May 2013]

TRH links:

LOC124906284 (HGNC:):

LOC124906284 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005417675).

BP6

Variant 3-129975838-C-G is Benign according to our data. Variant chr3-129975838-C-G is described in ClinVar as [Benign]. Clinvar id is 260114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.323 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRH	NM_007117.5 link	c.22C>G	p.Leu8Val	missense_variant	Exon 2 of 3	ENST00000302649.4	NP_009048.1	P20396
LOC124906284		n.129975838C>G		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRH	ENST00000302649.4 link	c.22C>G	p.Leu8Val	missense_variant	Exon 2 of 3	1	NM_007117.5	ENSP00000303452.3		P20396

Frequencies

GnomAD3 genomes

AF:

0.150

AC:

22871

AN:

152176

Hom.:

2348

Cov.:

show subpopulations

Gnomad AFR

AF:

0.222

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.267

Gnomad ASJ

AF:

0.0772

Gnomad EAS

AF:

0.335

Gnomad SAS

AF:

0.167

Gnomad FIN

AF:

0.0837

Gnomad MID

AF:

0.123

Gnomad NFE

AF:

0.0807

Gnomad OTH

AF:

0.156

GnomAD2 exomes

AF:

0.154

AC:

36936

AN:

239362

AF XY:

0.146

show subpopulations

Gnomad AFR exome

AF:

0.222

Gnomad AMR exome

AF:

0.313

Gnomad ASJ exome

AF:

0.0850

Gnomad EAS exome

AF:

0.328

Gnomad FIN exome

AF:

0.0924

Gnomad NFE exome

AF:

0.0836

Gnomad OTH exome

AF:

0.137

GnomAD4 exome

AF:

0.104

AC:

151319

AN:

1456658

Hom.:

10797

Cov.:

AF XY:

0.104

AC XY:

75162

AN XY:

724452

show subpopulations

African (AFR)

AF:

0.224

AC:

7481

AN:

33346

American (AMR)

AF:

0.307

AC:

13572

AN:

44258

Ashkenazi Jewish (ASJ)

AF:

0.0835

AC:

2174

AN:

26046

East Asian (EAS)

AF:

0.330

AC:

13028

AN:

39534

South Asian (SAS)

AF:

0.156

AC:

13355

AN:

85706

European-Finnish (FIN)

AF:

0.0931

AC:

4880

AN:

52434

Middle Eastern (MID)

AF:

0.130

AC:

583

AN:

4492

European-Non Finnish (NFE)

AF:

0.0803

AC:

89142

AN:

1110764

Other (OTH)

AF:

0.118

AC:

7104

AN:

60078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

7221

14442

21662

28883

36104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3682

7364

11046

14728

18410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.150

AC:

22918

AN:

152294

Hom.:

2354

Cov.:

AF XY:

0.156

AC XY:

11594

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.222

AC:

9244

AN:

41556

American (AMR)

AF:

0.268

AC:

4098

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0772

AC:

268

AN:

3472

East Asian (EAS)

AF:

0.336

AC:

1736

AN:

5166

South Asian (SAS)

AF:

0.168

AC:

810

AN:

4832

European-Finnish (FIN)

AF:

0.0837

AC:

889

AN:

10622

Middle Eastern (MID)

AF:

0.119

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0807

AC:

5489

AN:

68026

Other (OTH)

AF:

0.156

AC:

331

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

947

1894

2841

3788

4735

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

238

476

714

952

1190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0974

Hom.:

282

Bravo

AF:

0.166

TwinsUK

AF:

0.0823

AC:

305

ALSPAC

AF:

0.0864

AC:

333

ESP6500AA

AF:

0.203

AC:

869

ESP6500EA

AF:

0.0796

AC:

669

ExAC

AF:

0.143

AC:

17278

Asia WGS

AF:

0.274

AC:

951

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

T;.

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.71

T;T

MetaRNN

Benign

0.0054

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.6

M;.

PhyloP100

1.9

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.0

N;N

REVEL

Benign

0.040

Sift

Uncertain

0.023

D;D

Sift4G

Benign

0.078

T;T

Polyphen

0.76

P;.

Vest4

0.17

MPC

0.42

ClinPred

0.014

GERP RS

2.2

Varity_R

0.10

gMVP

0.37

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over