Variant 3-129975838-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

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

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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. Variant chr3-129975838-C-G is described in Lovd as [Benign].

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/exons	MANE	UniProt
TRH	NM_007117.5 linkuse as main transcript	c.22C>G	p.Leu8Val	missense_variant	2/3	ENST00000302649.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRH	ENST00000302649.4 linkuse as main transcript	c.22C>G	p.Leu8Val	missense_variant	2/3	1	NM_007117.5	P2
TRH	ENST00000507066.1 linkuse as main transcript	c.22C>G	p.Leu8Val	missense_variant	2/3	5		A1

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

GnomAD3 exomes

AF:

0.154

AC:

36936

AN:

239362

Hom.:

3957

AF XY:

0.146

AC XY:

19070

AN XY:

130806

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 SAS exome

AF:

0.159

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

Gnomad4 AFR exome

AF:

0.224

Gnomad4 AMR exome

AF:

0.307

Gnomad4 ASJ exome

AF:

0.0835

Gnomad4 EAS exome

AF:

0.330

Gnomad4 SAS exome

AF:

0.156

Gnomad4 FIN exome

AF:

0.0931

Gnomad4 NFE exome

AF:

0.0803

Gnomad4 OTH exome

AF:

0.118

GnomAD4 genome

AF:

0.150

AC:

22918

AN:

152294

Hom.:

2354

Cov.:

AF XY:

0.156

AC XY:

11594

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.222

Gnomad4 AMR

AF:

0.268

Gnomad4 ASJ

AF:

0.0772

Gnomad4 EAS

AF:

0.336

Gnomad4 SAS

AF:

0.168

Gnomad4 FIN

AF:

0.0837

Gnomad4 NFE

AF:

0.0807

Gnomad4 OTH

AF:

0.156

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

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

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;.

MutationTaster

Benign

0.89

P;P

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over