Genetic Variant TRHR:p.Val41Val (chr8-109087635-A-G) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_003301.7(TRHR):c.123A>G(p.Val41Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00352 in 1,614,168 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0022 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 9 hom. )

Consequence

TRHR
NM_003301.7 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.459

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

hypothyroidism, congenital, nongoitrous, 7
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
resistance to thyrotropin-releasing hormone syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TRHR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant 8-109087635-A-G is Benign according to our data. Variant chr8-109087635-A-G is described in ClinVar as Benign. ClinVar VariationId is 715012.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.459 with no splicing effect.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003301.7. 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
	TRHR	NM_003301.7	MANE Select	c.123A>G	p.Val41Val	synonymous	Exon 2 of 3	NP_003292.1	P34981

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRHR	ENST00000518632.2	TSL:5 MANE Select	c.123A>G	p.Val41Val	synonymous	Exon 2 of 3	ENSP00000430711.2	P34981
	TRHR	ENST00000311762.2	TSL:1	c.123A>G	p.Val41Val	synonymous	Exon 1 of 2	ENSP00000309818.2	P34981

Frequencies

GnomAD3 genomes

AF:

0.00217

AC:

330

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00424

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00378

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00209

AC:

526

AN:

251386

AF XY:

0.00216

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00319

Gnomad NFE exome

AF:

0.00357

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00366

AC:

5352

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00352

AC XY:

2562

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33480

American (AMR)

AF:

0.000224

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000661

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00324

AC:

173

AN:

53420

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00447

AC:

4974

AN:

1112010

Other (OTH)

AF:

0.00205

AC:

124

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

369

738

1107

1476

1845

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

184

368

552

736

920

<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:

0.00217

AC:

330

AN:

152282

Hom.:

Cov.:

AF XY:

0.00212

AC XY:

158

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.000505

AC:

AN:

41556

American (AMR)

AF:

0.0000654

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000622

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00424

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00378

AC:

257

AN:

68030

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00286

Hom.:

Bravo

AF:

0.00177

EpiCase

AF:

0.00316

EpiControl

AF:

0.00302

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

TRHR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

7.2

(source)

DANN

Benign

0.65

PhyloP100

0.46

PromoterAI

0.0098

Neutral

(source)

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over