8-25423284-C-G

Position:

chr8-25423284-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001083111.2(GNRH1):c.47G>C(p.Trp16Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 1,609,944 control chromosomes in the GnomAD database, including 50,204 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 3916 hom., cov: 32)

Exomes 𝑓: 0.24 ( 46288 hom. )

Consequence

GNRH1
NM_001083111.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.36

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.604127E-4).

BP6

Variant 8-25423284-C-G is Benign according to our data. Variant chr8-25423284-C-G is described in ClinVar as [Benign]. Clinvar id is 362652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-25423284-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.534 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNRH1	NM_001083111.2 linkuse as main transcript	c.47G>C	p.Trp16Ser	missense_variant	2/4	ENST00000421054.7
GNRH1	NM_000825.3 linkuse as main transcript	c.59G>C	p.Trp20Ser	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNRH1	ENST00000421054.7 linkuse as main transcript	c.47G>C	p.Trp16Ser	missense_variant	2/4	1	NM_001083111.2	P1
GNRH1	ENST00000276414.4 linkuse as main transcript	c.47G>C	p.Trp16Ser	missense_variant	1/3	1		P1

Frequencies

GnomAD3 genomes

AF:

0.206

AC:

31261

AN:

152034

Hom.:

3918

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0830

Gnomad AMI

AF:

0.242

Gnomad AMR

AF:

0.184

Gnomad ASJ

AF:

0.263

Gnomad EAS

AF:

0.551

Gnomad SAS

AF:

0.124

Gnomad FIN

AF:

0.276

Gnomad MID

AF:

0.212

Gnomad NFE

AF:

0.250

Gnomad OTH

AF:

0.216

GnomAD3 exomes

AF:

0.232

AC:

57704

AN:

249258

Hom.:

8206

AF XY:

0.229

AC XY:

30955

AN XY:

135228

show subpopulations

Gnomad AFR exome

AF:

0.0837

Gnomad AMR exome

AF:

0.140

Gnomad ASJ exome

AF:

0.265

Gnomad EAS exome

AF:

0.543

Gnomad SAS exome

AF:

0.123

Gnomad FIN exome

AF:

0.277

Gnomad NFE exome

AF:

0.248

Gnomad OTH exome

AF:

0.231

GnomAD4 exome

AF:

0.242

AC:

352936

AN:

1457792

Hom.:

46288

Cov.:

AF XY:

0.239

AC XY:

173556

AN XY:

725464

show subpopulations

Gnomad4 AFR exome

AF:

0.0767

Gnomad4 AMR exome

AF:

0.146

Gnomad4 ASJ exome

AF:

0.269

Gnomad4 EAS exome

AF:

0.528

Gnomad4 SAS exome

AF:

0.124

Gnomad4 FIN exome

AF:

0.278

Gnomad4 NFE exome

AF:

0.248

Gnomad4 OTH exome

AF:

0.241

GnomAD4 genome

AF:

0.205

AC:

31240

AN:

152152

Hom.:

3916

Cov.:

AF XY:

0.207

AC XY:

15375

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.0829

Gnomad4 AMR

AF:

0.184

Gnomad4 ASJ

AF:

0.263

Gnomad4 EAS

AF:

0.550

Gnomad4 SAS

AF:

0.122

Gnomad4 FIN

AF:

0.276

Gnomad4 NFE

AF:

0.250

Gnomad4 OTH

AF:

0.216

Alfa

AF:

0.250

Hom.:

3860

Bravo

AF:

0.198

TwinsUK

AF:

0.253

AC:

939

ALSPAC

AF:

0.256

AC:

985

ESP6500AA

AF:

0.0924

AC:

348

ESP6500EA

AF:

0.251

AC:

2064

ExAC

AF:

0.233

AC:

28150

Asia WGS

AF:

0.292

AC:

1012

AN:

3478

EpiCase

AF:

0.254

EpiControl

AF:

0.239

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 16, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Hypogonadotropic hypogonadism 12 with or without anosmia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.58

DEOGEN2

Benign

0.12

T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.058

MetaRNN

Benign

0.00026

T;T

MetaSVM

Benign

-0.92

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.27

PROVEAN

Benign

0.18

N;N

REVEL

Benign

0.092

Sift

Benign

0.093

T;T

Sift4G

Benign

0.43

T;T

Polyphen

0.0020

B;B

Vest4

0.11

MPC

0.31

ClinPred

0.013

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.093

gMVP

0.34

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over