NM_007117.5:c.248G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBS1BS2

The NM_007117.5(TRH):c.248G>A(p.Arg83His) variant causes a missense change. The variant allele was found at a frequency of 0.00199 in 1,613,804 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0092 ( 22 hom., cov: 31)

Exomes 𝑓: 0.0012 ( 23 hom. )

Consequence

TRH
NM_007117.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 5.04

Publications

5 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 -19 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 8: BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, PROVEAN, REVEL, REVEL [when AlphaMissense, BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.01296562).

BP6

Variant 3-129976735-G-A is Benign according to our data. Variant chr3-129976735-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00923 (1403/152052) while in subpopulation AFR AF = 0.0298 (1235/41454). AF 95% confidence interval is 0.0284. There are 22 homozygotes in GnomAd4. There are 642 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 22 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007117.5. 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
	TRH	NM_007117.5	MANE Select	c.248G>A	p.Arg83His	missense	Exon 3 of 3	NP_009048.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TRH	ENST00000302649.4	TSL:1 MANE Select	c.248G>A	p.Arg83His	missense	Exon 3 of 3	ENSP00000303452.3
TRH	ENST00000507066.1	TSL:5	c.236G>A	p.Arg79His	missense	Exon 3 of 3	ENSP00000426522.1
ENSG00000250643	ENST00000785099.1		n.298-4627C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00920

AC:

1398

AN:

151934

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0297

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00728

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.00270

AC:

678

AN:

251276

AF XY:

0.00237

show subpopulations

Gnomad AFR exome

AF:

0.0299

Gnomad AMR exome

AF:

0.00289

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000352

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00124

AC:

1811

AN:

1461752

Hom.:

Cov.:

AF XY:

0.00115

AC XY:

836

AN XY:

727170

show subpopulations

African (AFR)

AF:

0.0319

AC:

1068

AN:

33472

American (AMR)

AF:

0.00358

AC:

160

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00165

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000545

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00399

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000241

AC:

268

AN:

1111940

Other (OTH)

AF:

0.00334

AC:

202

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

119

239

358

478

597

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<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:

0.00923

AC:

1403

AN:

152052

Hom.:

Cov.:

AF XY:

0.00864

AC XY:

642

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.0298

AC:

1235

AN:

41454

American (AMR)

AF:

0.00720

AC:

110

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3470

East Asian (EAS)

AF:

0.000195

AC:

AN:

5134

South Asian (SAS)

AF:

0.000208

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000338

AC:

AN:

67996

Other (OTH)

AF:

0.0109

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

130

194

259

324

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00311

Hom.:

Bravo

AF:

0.0109

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.0309

AC:

136

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.00323

AC:

392

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000652

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.028

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.64

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.87

MetaRNN

Benign

0.013

MetaSVM

Uncertain

-0.27

MutationAssessor

Pathogenic

3.0

PhyloP100

5.0

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-4.5

REVEL

Pathogenic

0.66

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.67

MVP

0.91

MPC

0.52

ClinPred

0.028

GERP RS

5.0

Varity_R

0.69

gMVP

0.23

Mutation Taster

=87/13

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over