rs4986942

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_000406.3(GNRHR):c.453C>T(p.Ser151Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0859 in 1,613,558 control chromosomes in the GnomAD database, including 6,507 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.085 ( 638 hom., cov: 32)

Exomes 𝑓: 0.086 ( 5869 hom. )

Consequence

GNRHR
NM_000406.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.13

Publications

14 publications found

Variant links:

Genes affected

GNRHR (HGNC:4421): (gonadotropin releasing hormone receptor) This gene encodes the receptor for type 1 gonadotropin-releasing hormone. This receptor is a member of the seven-transmembrane, G-protein coupled receptor (GPCR) family. It is expressed on the surface of pituitary gonadotrope cells as well as lymphocytes, breast, ovary, and prostate. Following binding of gonadotropin-releasing hormone, the receptor associates with G-proteins that activate a phosphatidylinositol-calcium second messenger system. Activation of the receptor ultimately causes the release of gonadotropic luteinizing hormone (LH) and follicle stimulating hormone (FSH). Defects in this gene are a cause of hypogonadotropic hypogonadism (HH). Alternative splicing results in multiple transcript variants encoding different isoforms. More than 18 transcription initiation sites in the 5' region and multiple polyA signals in the 3' region have been identified for this gene. [provided by RefSeq, Jul 2008]

GNRHR links:

UBA6-DT (HGNC:49083): (UBA6 divergent transcript)

UBA6-DT 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=-0.73).

BP6

Variant 4-67753883-G-A is Benign according to our data. Variant chr4-67753883-G-A is described in ClinVar as [Benign]. Clinvar id is 349456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.13 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNRHR	NM_000406.3 link	c.453C>T	p.Ser151Ser	synonymous_variant	Exon 1 of 3	ENST00000226413.5	NP_000397.1	P30968-1
GNRHR	NM_001012763.2 link	c.453C>T	p.Ser151Ser	synonymous_variant	Exon 1 of 3		NP_001012781.1	P30968-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNRHR	ENST00000226413.5 link	c.453C>T	p.Ser151Ser	synonymous_variant	Exon 1 of 3	1	NM_000406.3	ENSP00000226413.5		P30968-1

Frequencies

GnomAD3 genomes

AF:

0.0853

AC:

12979

AN:

152130

Hom.:

636

Cov.:

show subpopulations

Gnomad AFR

AF:

0.105

Gnomad AMI

AF:

0.172

Gnomad AMR

AF:

0.0875

Gnomad ASJ

AF:

0.0879

Gnomad EAS

AF:

0.00635

Gnomad SAS

AF:

0.0534

Gnomad FIN

AF:

0.0282

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0892

Gnomad OTH

AF:

0.0823

GnomAD2 exomes

AF:

0.0755

AC:

18921

AN:

250604

AF XY:

0.0736

show subpopulations

Gnomad AFR exome

AF:

0.104

Gnomad AMR exome

AF:

0.0934

Gnomad ASJ exome

AF:

0.0839

Gnomad EAS exome

AF:

0.00571

Gnomad FIN exome

AF:

0.0325

Gnomad NFE exome

AF:

0.0905

Gnomad OTH exome

AF:

0.0798

GnomAD4 exome

AF:

0.0859

AC:

125590

AN:

1461310

Hom.:

5869

Cov.:

AF XY:

0.0843

AC XY:

61318

AN XY:

727010

show subpopulations

African (AFR)

AF:

0.102

AC:

3421

AN:

33476

American (AMR)

AF:

0.0941

AC:

4203

AN:

44658

Ashkenazi Jewish (ASJ)

AF:

0.0848

AC:

2216

AN:

26128

East Asian (EAS)

AF:

0.00658

AC:

261

AN:

39690

South Asian (SAS)

AF:

0.0533

AC:

4600

AN:

86250

European-Finnish (FIN)

AF:

0.0362

AC:

1932

AN:

53384

Middle Eastern (MID)

AF:

0.0883

AC:

509

AN:

5764

European-Non Finnish (NFE)

AF:

0.0932

AC:

103589

AN:

1111594

Other (OTH)

AF:

0.0805

AC:

4859

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

5882

11765

17647

23530

29412

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3854

7708

11562

15416

19270

<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:

0.0854

AC:

13002

AN:

152248

Hom.:

638

Cov.:

AF XY:

0.0812

AC XY:

6046

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.105

AC:

4346

AN:

41542

American (AMR)

AF:

0.0878

AC:

1342

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0879

AC:

305

AN:

3470

East Asian (EAS)

AF:

0.00637

AC:

AN:

5182

South Asian (SAS)

AF:

0.0539

AC:

260

AN:

4828

European-Finnish (FIN)

AF:

0.0282

AC:

299

AN:

10616

Middle Eastern (MID)

AF:

0.0748

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0892

AC:

6066

AN:

68000

Other (OTH)

AF:

0.0814

AC:

172

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

596

1191

1787

2382

2978

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

288

432

576

720

<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:

0.0915

Hom.:

1245

Bravo

AF:

0.0925

Asia WGS

AF:

0.0420

AC:

148

AN:

3478

EpiCase

AF:

0.0939

EpiControl

AF:

0.0881

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jul 27, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypogonadotropic hypogonadism 7 with or without anosmia

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

4.0

(source)

DANN

Benign

0.50

PhyloP100

1.1

PromoterAI

-0.065

Neutral

(source)

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