3-129977111-T-C

Variant names:

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.624T>C(p.Leu208Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.992 in 1,559,382 control chromosomes in the GnomAD database, including 768,447 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.96 ( 70518 hom., cov: 30)

Exomes 𝑓: 1.0 ( 697929 hom. )

Consequence

TRH
NM_007117.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.03

Publications

11 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=-0.86).

BP6

Variant 3-129977111-T-C is Benign according to our data. Variant chr3-129977111-T-C is described in ClinVar as Benign. ClinVar VariationId is 260116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.03 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRH	NM_007117.5 link	c.624T>C	p.Leu208Leu	synonymous_variant	Exon 3 of 3	ENST00000302649.4	NP_009048.1	P20396
LOC124906284		n.129977111T>C		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRH	ENST00000302649.4 link	c.624T>C	p.Leu208Leu	synonymous_variant	Exon 3 of 3	1	NM_007117.5	ENSP00000303452.3		P20396

Frequencies

GnomAD3 genomes

AF:

0.962

AC:

146087

AN:

151932

Hom.:

70477

Cov.:

show subpopulations

Gnomad AFR

AF:

0.870

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.981

Gnomad ASJ

AF:

0.992

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.999

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.991

Gnomad NFE

AF:

0.999

Gnomad OTH

AF:

0.962

GnomAD2 exomes

AF:

0.988

AC:

207976

AN:

210400

AF XY:

0.991

show subpopulations

Gnomad AFR exome

AF:

0.862

Gnomad AMR exome

AF:

0.993

Gnomad ASJ exome

AF:

0.993

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

0.999

Gnomad OTH exome

AF:

0.993

GnomAD4 exome

AF:

0.996

AC:

1401244

AN:

1407332

Hom.:

697929

Cov.:

AF XY:

0.996

AC XY:

692487

AN XY:

695202

show subpopulations

African (AFR)

AF:

0.856

AC:

26503

AN:

30976

American (AMR)

AF:

0.990

AC:

34003

AN:

34334

Ashkenazi Jewish (ASJ)

AF:

0.994

AC:

22590

AN:

22734

East Asian (EAS)

AF:

1.00

AC:

39164

AN:

39164

South Asian (SAS)

AF:

1.00

AC:

77964

AN:

77994

European-Finnish (FIN)

AF:

1.00

AC:

51518

AN:

51518

Middle Eastern (MID)

AF:

0.992

AC:

5329

AN:

5374

European-Non Finnish (NFE)

AF:

1.00

AC:

1087063

AN:

1087502

Other (OTH)

AF:

0.989

AC:

57110

AN:

57736

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

344

688

1031

1375

1719

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21586

43172

64758

86344

107930

<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:

0.961

AC:

146187

AN:

152050

Hom.:

70518

Cov.:

AF XY:

0.963

AC XY:

71576

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.870

AC:

36067

AN:

41468

American (AMR)

AF:

0.981

AC:

15013

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.992

AC:

3443

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5051

AN:

5052

South Asian (SAS)

AF:

1.00

AC:

4823

AN:

4824

European-Finnish (FIN)

AF:

1.00

AC:

10624

AN:

10624

Middle Eastern (MID)

AF:

0.990

AC:

291

AN:

294

European-Non Finnish (NFE)

AF:

0.999

AC:

67929

AN:

67982

Other (OTH)

AF:

0.962

AC:

2034

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

262

524

785

1047

1309

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

908

1816

2724

3632

4540

<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:

0.987

Hom.:

167610

Bravo

AF:

0.955

Asia WGS

AF:

0.990

AC:

3441

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hypothalamic hypothyroidism

Benign:1

Sep 10, 2021

Genome-Nilou Lab

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

-0.86

CADD

Benign

0.74

(source)

DANN

Benign

0.44

PhyloP100

-1.0

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