8-25423190-C-G

Position:

chr8-25423190-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2

The NM_001083111.2(GNRH1):c.141G>C(p.Glu47Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,606,844 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0016 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0020 ( 8 hom. )

Consequence

GNRH1
NM_001083111.2 missense, splice_region

Scores

Splicing: ADA: 0.9998

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 2.05

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 Likely_benign. Variant got -5 ACMG points.

BP6

Variant 8-25423190-C-G is Benign according to our data. Variant chr8-25423190-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 734969.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}.

BS2

High Homozygotes in GnomAd4 at 3 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNRH1	NM_001083111.2 linkuse as main transcript	c.141G>C	p.Glu47Asp	missense_variant, splice_region_variant	2/4	ENST00000421054.7	NP_001076580.1	P01148
GNRH1	NM_000825.3 linkuse as main transcript	c.153G>C	p.Glu51Asp	missense_variant, splice_region_variant	1/3		NP_000816.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNRH1	ENST00000421054.7 linkuse as main transcript	c.141G>C	p.Glu47Asp	missense_variant, splice_region_variant	2/4	1	NM_001083111.2	ENSP00000391280.2		P01148
GNRH1	ENST00000276414.4 linkuse as main transcript	c.141G>C	p.Glu47Asp	missense_variant, splice_region_variant	1/3	1		ENSP00000276414.4		P01148

Frequencies

GnomAD3 genomes

AF:

0.00158

AC:

241

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.0186

Gnomad AMR

AF:

0.00255

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0191

Gnomad NFE

AF:

0.00235

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.00153

AC:

381

AN:

249296

Hom.:

AF XY:

0.00168

AC XY:

227

AN XY:

135248

show subpopulations

Gnomad AFR exome

AF:

0.000194

Gnomad AMR exome

AF:

0.00157

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00203

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00212

Gnomad OTH exome

AF:

0.00314

GnomAD4 exome

AF:

0.00201

AC:

2917

AN:

1454574

Hom.:

Cov.:

AF XY:

0.00202

AC XY:

1465

AN XY:

724162

show subpopulations

Gnomad4 AFR exome

AF:

0.000270

Gnomad4 AMR exome

AF:

0.00159

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00197

Gnomad4 FIN exome

AF:

0.000262

Gnomad4 NFE exome

AF:

0.00221

Gnomad4 OTH exome

AF:

0.00256

GnomAD4 genome

AF:

0.00158

AC:

240

AN:

152270

Hom.:

Cov.:

AF XY:

0.00149

AC XY:

111

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.00255

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00235

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.00192

Hom.:

Bravo

AF:

0.00158

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000545

AC:

ESP6500EA

AF:

0.00208

AC:

ExAC

AF:

0.00140

AC:

169

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00240

EpiControl

AF:

0.00314

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	GNRH1: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -

Hypogonadotropic hypogonadism 12 with or without anosmia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.44

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;T

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.76

.;T

M_CAP

Benign

0.031

MetaRNN

Benign

0.0065

T;T

MetaSVM

Benign

-0.54

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.78

N;N

REVEL

Benign

0.12

Sift

Benign

0.14

T;T

Sift4G

Benign

0.19

T;T

Polyphen

1.0

D;D

Vest4

0.087

MutPred

0.30

Gain of ubiquitination at K50 (P = 0.1106);Gain of ubiquitination at K50 (P = 0.1106);

MVP

0.53

MPC

0.73

ClinPred

0.040

GERP RS

5.5

Varity_R

0.22

gMVP

0.13

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

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

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