Variant chr8-25419460-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP3BP6_ModerateBS1BS2

The NM_001083111.2(GNRH1):c.238G>C(p.Glu80Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,415,232 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 Benign (★).

Frequency

Genomes: 𝑓 0.0054 ( 6 hom., cov: 32)

Exomes 𝑓: 0.00054 ( 5 hom. )

Consequence

GNRH1
NM_001083111.2 missense, splice_region

Scores

Splicing: ADA: 0.9771

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.99

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BP6

Variant 8-25419460-C-G is Benign according to our data. Variant chr8-25419460-C-G is described in ClinVar as [Benign]. Clinvar id is 773401.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00542 (825/152148) while in subpopulation AFR AF= 0.019 (789/41488). AF 95% confidence interval is 0.0179. There are 6 homozygotes in gnomad4. There are 375 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNRH1	NM_001083111.2 linkuse as main transcript	c.238G>C	p.Glu80Gln	missense_variant, splice_region_variant	4/4	ENST00000421054.7
GNRH1	NM_000825.3 linkuse as main transcript	c.250G>C	p.Glu84Gln	missense_variant, splice_region_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNRH1	ENST00000421054.7 linkuse as main transcript	c.238G>C	p.Glu80Gln	missense_variant, splice_region_variant	4/4	1	NM_001083111.2	P1
GNRH1	ENST00000276414.4 linkuse as main transcript	c.238G>C	p.Glu80Gln	missense_variant, splice_region_variant	3/3	1		P1

Frequencies

GnomAD3 genomes

AF:

0.00542

AC:

824

AN:

152030

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0190

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00527

GnomAD3 exomes

AF:

0.00141

AC:

351

AN:

249030

Hom.:

AF XY:

0.00104

AC XY:

141

AN XY:

135162

show subpopulations

Gnomad AFR exome

AF:

0.0205

Gnomad AMR exome

AF:

0.000522

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000974

Gnomad OTH exome

AF:

0.000661

GnomAD4 exome

AF:

0.000542

AC:

685

AN:

1263084

Hom.:

Cov.:

AF XY:

0.000468

AC XY:

299

AN XY:

638486

show subpopulations

Gnomad4 AFR exome

AF:

0.0193

Gnomad4 AMR exome

AF:

0.000697

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000243

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000215

Gnomad4 OTH exome

AF:

0.00110

GnomAD4 genome

AF:

0.00542

AC:

825

AN:

152148

Hom.:

Cov.:

AF XY:

0.00504

AC XY:

375

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.0190

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00522

Alfa

AF:

0.000826

Hom.:

Bravo

AF:

0.00614

ESP6500AA

AF:

0.0194

AC:

ESP6500EA

AF:

0.000246

AC:

ExAC

AF:

0.00164

AC:

198

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.70

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;T

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.96

M_CAP

Benign

0.012

MetaRNN

Benign

0.0063

T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

0.78

N;N

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.77

N;N

REVEL

Benign

0.088

Sift

Benign

0.19

T;T

Sift4G

Benign

0.43

T;T

Polyphen

0.93

P;P

Vest4

0.12

MVP

0.33

MPC

0.52

ClinPred

0.027

GERP RS

3.4

Varity_R

0.097

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.76

SpliceAI score (max)

0.070

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