Variant 8-109119324-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_003301.7(TRHR):c.1066G>A(p.Val356Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00175 in 1,612,376 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 4 hom. )

Consequence

TRHR
NM_003301.7 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 4.67

Variant links:

Genes affected

TRHR (HGNC:12299): (thyrotropin releasing hormone receptor) This gene encodes a G protein-coupled receptor for thyrotropin-releasing hormone (TRH). Upon binding to TRH, this receptor activates the inositol phospholipid-calcium-protein kinase C transduction pathway. Mutations in this gene have been associated with generalized thyrotropin-releasing hormone resistance. [provided by RefSeq, Sep 2011]

TRHR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0074428916).

BP6

Variant 8-109119324-G-A is Benign according to our data. Variant chr8-109119324-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 721055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-109119324-G-A is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRHR	NM_003301.7 linkuse as main transcript	c.1066G>A	p.Val356Ile	missense_variant	3/3	ENST00000518632.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRHR	ENST00000518632.2 linkuse as main transcript	c.1066G>A	p.Val356Ile	missense_variant	3/3	5	NM_003301.7	P1
TRHR	ENST00000311762.2 linkuse as main transcript	c.1066G>A	p.Val356Ile	missense_variant	2/2	1		P1

Frequencies

GnomAD3 genomes

AF:

0.00176

AC:

267

AN:

151626

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00189

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00165

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00237

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00196

Gnomad OTH

AF:

0.00288

GnomAD3 exomes

AF:

0.00162

AC:

406

AN:

250066

Hom.:

AF XY:

0.00169

AC XY:

229

AN XY:

135110

show subpopulations

Gnomad AFR exome

AF:

0.00142

Gnomad AMR exome

AF:

0.000726

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000425

Gnomad FIN exome

AF:

0.00200

Gnomad NFE exome

AF:

0.00259

Gnomad OTH exome

AF:

0.00164

GnomAD4 exome

AF:

0.00175

AC:

2558

AN:

1460634

Hom.:

Cov.:

AF XY:

0.00171

AC XY:

1240

AN XY:

726642

show subpopulations

Gnomad4 AFR exome

AF:

0.00153

Gnomad4 AMR exome

AF:

0.000829

Gnomad4 ASJ exome

AF:

0.0000768

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000383

Gnomad4 FIN exome

AF:

0.00229

Gnomad4 NFE exome

AF:

0.00198

Gnomad4 OTH exome

AF:

0.00182

GnomAD4 genome

AF:

0.00176

AC:

267

AN:

151742

Hom.:

Cov.:

AF XY:

0.00171

AC XY:

127

AN XY:

74134

show subpopulations

Gnomad4 AFR

AF:

0.00188

Gnomad4 AMR

AF:

0.00165

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00237

Gnomad4 NFE

AF:

0.00196

Gnomad4 OTH

AF:

0.00285

Alfa

AF:

0.00170

Hom.:

Bravo

AF:

0.00177

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00208

AC:

253

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00262

EpiControl

AF:

0.00302

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	TRHR: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.22

T;T

Eigen

Benign

-0.029

Eigen_PC

Benign

0.067

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.69

.;T

M_CAP

Benign

0.050

MetaRNN

Benign

0.0074

T;T

MetaSVM

Benign

-0.69

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.61

N;N

REVEL

Benign

0.16

Sift

Benign

0.077

T;T

Sift4G

Uncertain

0.038

D;D

Polyphen

0.45

B;B

Vest4

0.057

MVP

0.71

MPC

0.19

ClinPred

0.017

GERP RS

4.9

Varity_R

0.082

gMVP

0.28

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