Variant 8-25423282-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001083111.2(GNRH1):c.49T>C(p.Cys17Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,459,990 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

GNRH1
NM_001083111.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.65

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNRH1	NM_001083111.2 linkuse as main transcript	c.49T>C	p.Cys17Arg	missense_variant	2/4	ENST00000421054.7	NP_001076580.1	P01148
GNRH1	NM_000825.3 linkuse as main transcript	c.61T>C	p.Cys21Arg	missense_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.49T>C	p.Cys17Arg	missense_variant	2/4	1	NM_001083111.2	ENSP00000391280.2		P01148
GNRH1	ENST00000276414.4 linkuse as main transcript	c.49T>C	p.Cys17Arg	missense_variant	1/3	1		ENSP00000276414.4		P01148

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249306

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135248

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1459990

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726492

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2024

The c.61T>C (p.C21R) alteration is located in exon 1 (coding exon 1) of the GNRH1 gene. This alteration results from a T to C substitution at nucleotide position 61, causing the cysteine (C) at amino acid position 21 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Benign

-0.0052

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Uncertain

0.67

D;D

Eigen

Benign

-0.090

Eigen_PC

Benign

-0.19

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.60

.;T

M_CAP

Benign

0.015

MetaRNN

Uncertain

0.57

D;D

MetaSVM

Benign

-0.90

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.7

D;D

REVEL

Uncertain

0.30

Sift

Uncertain

0.0060

D;D

Sift4G

Benign

0.083

T;T

Polyphen

0.99

D;D

Vest4

0.49

MutPred

0.54

Gain of MoRF binding (P = 0.0155);Gain of MoRF binding (P = 0.0155);

MVP

0.61

MPC

0.95

ClinPred

0.59

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.75

gMVP

0.18

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