Genetic Variant TRH:p.Asp128Asp (chr3-129976871-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_007117.5(TRH):c.384T>C(p.Asp128Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0697 in 1,612,116 control chromosomes in the GnomAD database, including 4,432 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.072 ( 445 hom., cov: 30)

Exomes 𝑓: 0.070 ( 3987 hom. )

Consequence

TRH
NM_007117.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.978

Publications

8 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 3-129976871-T-C is Benign according to our data. Variant chr3-129976871-T-C is described in ClinVar as [Benign]. Clinvar id is 260115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.978 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0973 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRH	NM_007117.5 link	c.384T>C	p.Asp128Asp	synonymous_variant	Exon 3 of 3	ENST00000302649.4	NP_009048.1	P20396
LOC124906284		n.129976871T>C		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRH	ENST00000302649.4 link	c.384T>C	p.Asp128Asp	synonymous_variant	Exon 3 of 3	1	NM_007117.5	ENSP00000303452.3		P20396

Frequencies

GnomAD3 genomes

AF:

0.0717

AC:

10755

AN:

150098

Hom.:

445

Cov.:

show subpopulations

Gnomad AFR

AF:

0.100

Gnomad AMI

AF:

0.00221

Gnomad AMR

AF:

0.0682

Gnomad ASJ

AF:

0.0573

Gnomad EAS

AF:

0.00240

Gnomad SAS

AF:

0.0174

Gnomad FIN

AF:

0.0432

Gnomad MID

AF:

0.0517

Gnomad NFE

AF:

0.0702

Gnomad OTH

AF:

0.0802

GnomAD2 exomes

AF:

0.0547

AC:

13756

AN:

251414

AF XY:

0.0540

show subpopulations

Gnomad AFR exome

AF:

0.103

Gnomad AMR exome

AF:

0.0473

Gnomad ASJ exome

AF:

0.0583

Gnomad EAS exome

AF:

0.00506

Gnomad FIN exome

AF:

0.0406

Gnomad NFE exome

AF:

0.0699

Gnomad OTH exome

AF:

0.0645

GnomAD4 exome

AF:

0.0695

AC:

101641

AN:

1461892

Hom.:

3987

Cov.:

AF XY:

0.0680

AC XY:

49427

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.0998

AC:

3342

AN:

33480

American (AMR)

AF:

0.0506

AC:

2264

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0568

AC:

1485

AN:

26136

East Asian (EAS)

AF:

0.00174

AC:

AN:

39700

South Asian (SAS)

AF:

0.0191

AC:

1649

AN:

86258

European-Finnish (FIN)

AF:

0.0422

AC:

2254

AN:

53418

Middle Eastern (MID)

AF:

0.0482

AC:

278

AN:

5768

European-Non Finnish (NFE)

AF:

0.0775

AC:

86176

AN:

1112012

Other (OTH)

AF:

0.0683

AC:

4124

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

6995

13990

20986

27981

34976

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3214

6428

9642

12856

16070

<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:

0.0716

AC:

10762

AN:

150224

Hom.:

445

Cov.:

AF XY:

0.0691

AC XY:

5065

AN XY:

73296

show subpopulations

African (AFR)

AF:

0.0998

AC:

4070

AN:

40764

American (AMR)

AF:

0.0681

AC:

1031

AN:

15130

Ashkenazi Jewish (ASJ)

AF:

0.0573

AC:

198

AN:

3454

East Asian (EAS)

AF:

0.00261

AC:

AN:

4984

South Asian (SAS)

AF:

0.0172

AC:

AN:

4712

European-Finnish (FIN)

AF:

0.0432

AC:

449

AN:

10390

Middle Eastern (MID)

AF:

0.0515

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.0702

AC:

4739

AN:

67532

Other (OTH)

AF:

0.0793

AC:

165

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

490

980

1471

1961

2451

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

118

236

354

472

590

<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:

0.0697

Hom.:

407

Bravo

AF:

0.0754

Asia WGS

AF:

0.0190

AC:

AN:

3478

EpiCase

AF:

0.0775

EpiControl

AF:

0.0809

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

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.53

(source)

DANN

Benign

0.35

PhyloP100

-0.98

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