8-25419428-C-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_001083111.2(GNRH1):c.270G>T(p.Lys90Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000199 in 1,490,520 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

GNRH1
NM_001083111.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.27

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 -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.051069677).

BP6

Variant 8-25419428-C-A is Benign according to our data. Variant chr8-25419428-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1373135.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNRH1	NM_001083111.2 linkuse as main transcript	c.270G>T	p.Lys90Asn	missense_variant	4/4	ENST00000421054.7
GNRH1	NM_000825.3 linkuse as main transcript	c.282G>T	p.Lys94Asn	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNRH1	ENST00000421054.7 linkuse as main transcript	c.270G>T	p.Lys90Asn	missense_variant	4/4	1	NM_001083111.2	P1
GNRH1	ENST00000276414.4 linkuse as main transcript	c.270G>T	p.Lys90Asn	missense_variant	3/3	1		P1

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000213

AC:

AN:

249298

Hom.:

AF XY:

0.000266

AC XY:

AN XY:

135284

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000318

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.000200

AC:

267

AN:

1338260

Hom.:

Cov.:

AF XY:

0.000216

AC XY:

145

AN XY:

672668

show subpopulations

Gnomad4 AFR exome

AF:

0.0000967

Gnomad4 AMR exome

AF:

0.0000449

Gnomad4 ASJ exome

AF:

0.000867

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000597

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000220

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000197

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000259

Hom.:

Bravo

AF:

0.000204

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000123

AC:

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 28, 2023	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 94 of the GNRH1 protein (p.Lys94Asn). This variant is present in population databases (rs372089839, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with GNRH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1373135). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	GNRH1: BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.50

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.60

D;D

Eigen

Benign

0.039

Eigen_PC

Benign

0.075

FATHMM_MKL

Uncertain

0.93

M_CAP

Benign

0.028

MetaRNN

Benign

0.051

T;T

MetaSVM

Benign

-0.97

MutationTaster

Benign

0.98

D;D

PrimateAI

Benign

0.40

PROVEAN

Benign

-2.0

N;N

REVEL

Benign

0.066

Sift

Uncertain

0.0030

D;D

Sift4G

Benign

0.099

T;T

Polyphen

0.76

P;P

Vest4

0.20

MutPred

0.33

Loss of ubiquitination at K90 (P = 0.0063);Loss of ubiquitination at K90 (P = 0.0063);

MVP

0.24

MPC

0.52

ClinPred

0.080

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.25

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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