dbSNP rs6186: GNRH1:p.Phe61Phe (chr8-25421627-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001083111.2(GNRH1):c.183C>T(p.Phe61Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00643 in 1,606,116 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 29 hom., cov: 31)

Exomes 𝑓: 0.0058 ( 57 hom. )

Consequence

GNRH1
NM_001083111.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -3.82

Publications

7 publications found

Variant links:

Genes affected

GNRH1 (HGNC:4419): (gonadotropin releasing hormone 1) This gene encodes a preproprotein that is proteolytically processed to generate a peptide that is a member of the gonadotropin-releasing hormone (GnRH) family of peptides. Alternative splicing results in multiple transcript variants, at least one of which is secreted and then cleaved to generate gonadoliberin-1 and GnRH-associated peptide 1. Gonadoliberin-1 stimulates the release of luteinizing and follicle stimulating hormones, which are important for reproduction. Mutations in this gene are associated with hypogonadotropic hypogonadism. [provided by RefSeq, Nov 2015]

GNRH1 Gene-Disease associations (from GenCC):

hypogonadotropic hypogonadism 12 with or without anosmia
Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
hypogonadotropic hypogonadism
Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet

GNRH1 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=-0.89).

BP6

Variant 8-25421627-G-A is Benign according to our data. Variant chr8-25421627-G-A is described in ClinVar as Benign. ClinVar VariationId is 788272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.82 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0129 (1960/152196) while in subpopulation AFR AF = 0.0343 (1424/41504). AF 95% confidence interval is 0.0328. There are 29 homozygotes in GnomAd4. There are 933 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 29 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001083111.2. 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
	GNRH1	NM_001083111.2	MANE Select	c.183C>T	p.Phe61Phe	synonymous	Exon 3 of 4	NP_001076580.1	P01148
	GNRH1	NM_000825.3		c.195C>T	p.Phe65Phe	synonymous	Exon 2 of 3	NP_000816.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GNRH1	ENST00000421054.7	TSL:1 MANE Select	c.183C>T	p.Phe61Phe	synonymous	Exon 3 of 4	ENSP00000391280.2	P01148
GNRH1	ENST00000276414.4	TSL:1	c.183C>T	p.Phe61Phe	synonymous	Exon 2 of 3	ENSP00000276414.4	P01148
GNRH1	ENST00000966630.1		c.183C>T	p.Phe61Phe	synonymous	Exon 3 of 4	ENSP00000636689.1

Frequencies

GnomAD3 genomes

AF:

0.0128

AC:

1943

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0340

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00806

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00528

Gnomad OTH

AF:

0.0177

GnomAD2 exomes

AF:

0.00524

AC:

1304

AN:

248810

AF XY:

0.00477

show subpopulations

Gnomad AFR exome

AF:

0.0358

Gnomad AMR exome

AF:

0.00395

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00269

Gnomad NFE exome

AF:

0.00462

Gnomad OTH exome

AF:

0.00415

GnomAD4 exome

AF:

0.00575

AC:

8366

AN:

1453920

Hom.:

Cov.:

AF XY:

0.00555

AC XY:

4014

AN XY:

723754

show subpopulations

African (AFR)

AF:

0.0397

AC:

1321

AN:

33276

American (AMR)

AF:

0.00430

AC:

192

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.000192

AC:

AN:

26064

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39674

South Asian (SAS)

AF:

0.000209

AC:

AN:

85996

European-Finnish (FIN)

AF:

0.00296

AC:

158

AN:

53372

Middle Eastern (MID)

AF:

0.000934

AC:

AN:

4282

European-Non Finnish (NFE)

AF:

0.00573

AC:

6344

AN:

1106608

Other (OTH)

AF:

0.00539

AC:

323

AN:

59958

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

368

736

1104

1472

1840

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

276

552

828

1104

1380

<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:

0.0129

AC:

1960

AN:

152196

Hom.:

Cov.:

AF XY:

0.0125

AC XY:

933

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.0343

AC:

1424

AN:

41504

American (AMR)

AF:

0.00798

AC:

122

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00141

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00528

AC:

359

AN:

68016

Other (OTH)

AF:

0.0175

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

103

205

308

410

513

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.00825

Hom.:

Bravo

AF:

0.0141

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.00458

EpiControl

AF:

0.00427

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Hypogonadotropic hypogonadism 12 with or without anosmia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.091

(source)

DANN

Benign

0.83

PhyloP100

-3.8

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.010

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