8-25421627-G-A

Position:

chr8-25421627-G-A

Variant summary

Our verdict is Benign. Variant got -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:3

Conservation

PhyloP100: -3.82

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 -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 id 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 29 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNRH1	NM_001083111.2 linkuse as main transcript	c.183C>T	p.Phe61Phe	synonymous_variant	3/4	ENST00000421054.7	NP_001076580.1	P01148
GNRH1	NM_000825.3 linkuse as main transcript	c.195C>T	p.Phe65Phe	synonymous_variant	2/3		NP_000816.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNRH1	ENST00000421054.7 linkuse as main transcript	c.183C>T	p.Phe61Phe	synonymous_variant	3/4	1	NM_001083111.2	ENSP00000391280.2		P01148
GNRH1	ENST00000276414.4 linkuse as main transcript	c.183C>T	p.Phe61Phe	synonymous_variant	2/3	1		ENSP00000276414.4		P01148

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

GnomAD3 exomes

AF:

0.00524

AC:

1304

AN:

248810

Hom.:

AF XY:

0.00477

AC XY:

644

AN XY:

135016

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 SAS exome

AF:

0.000295

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

Gnomad4 AFR exome

AF:

0.0397

Gnomad4 AMR exome

AF:

0.00430

Gnomad4 ASJ exome

AF:

0.000192

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000209

Gnomad4 FIN exome

AF:

0.00296

Gnomad4 NFE exome

AF:

0.00573

Gnomad4 OTH exome

AF:

0.00539

GnomAD4 genome

AF:

0.0129

AC:

1960

AN:

152196

Hom.:

Cov.:

AF XY:

0.0125

AC XY:

933

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.0343

Gnomad4 AMR

AF:

0.00798

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00141

Gnomad4 NFE

AF:

0.00528

Gnomad4 OTH

AF:

0.0175

Alfa

AF:

0.00824

Hom.:

Bravo

AF:

0.0141

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.00458

EpiControl

AF:

0.00427

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	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hypogonadotropic hypogonadism 12 with or without anosmia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.091

DANN

Benign

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

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