rs776834867

Positions:

chr4-67754305-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1PP5BP4

The NM_000406.3(GNRHR):c.31C>A(p.Gln11Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,611,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

GNRHR
NM_000406.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.44

Variant links:

Genes affected

GNRHR (HGNC:4421): (gonadotropin releasing hormone receptor) This gene encodes the receptor for type 1 gonadotropin-releasing hormone. This receptor is a member of the seven-transmembrane, G-protein coupled receptor (GPCR) family. It is expressed on the surface of pituitary gonadotrope cells as well as lymphocytes, breast, ovary, and prostate. Following binding of gonadotropin-releasing hormone, the receptor associates with G-proteins that activate a phosphatidylinositol-calcium second messenger system. Activation of the receptor ultimately causes the release of gonadotropic luteinizing hormone (LH) and follicle stimulating hormone (FSH). Defects in this gene are a cause of hypogonadotropic hypogonadism (HH). Alternative splicing results in multiple transcript variants encoding different isoforms. More than 18 transcription initiation sites in the 5' region and multiple polyA signals in the 3' region have been identified for this gene. [provided by RefSeq, Jul 2008]

GNRHR links:

UBA6-DT (HGNC:49083): (UBA6 divergent transcript)

UBA6-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a topological_domain Extracellular (size 37) in uniprot entity GNRHR_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000406.3

PP5

Variant 4-67754305-G-T is Pathogenic according to our data. Variant chr4-67754305-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 349458.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

BP4

Computational evidence support a benign effect (MetaRNN=0.31918627). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNRHR	NM_000406.3 linkuse as main transcript	c.31C>A	p.Gln11Lys	missense_variant	1/3	ENST00000226413.5
GNRHR	NM_001012763.2 linkuse as main transcript	c.31C>A	p.Gln11Lys	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNRHR	ENST00000226413.5 linkuse as main transcript	c.31C>A	p.Gln11Lys	missense_variant	1/3	1	NM_000406.3	P1	P30968-1
UBA6-DT	ENST00000500538.7 linkuse as main transcript	n.1921-884G>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000129

AC:

AN:

247808

Hom.:

AF XY:

0.000156

AC XY:

AN XY:

134586

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000230

Gnomad OTH exome

AF:

0.000495

GnomAD4 exome

AF:

0.000134

AC:

196

AN:

1459614

Hom.:

Cov.:

AF XY:

0.000138

AC XY:

100

AN XY:

726218

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000580

Gnomad4 NFE exome

AF:

0.000162

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

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:

0.000474

Alfa

AF:

0.0000319

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.000173

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Isolated GnRH Deficiency

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

The c.31C>A (p.Gln11Lys) variant has been reported as part of a complex allele with the c.30T>A (p.Asn10Lys) variant, p.[Asn10Lys;Gln11Lys], in cis in six studies in which the complex allele is found in trans with a missense variant in a compound heterozygous state in at least eight isolated GnRH deficiency patients (Costa et al. 2001; Meysing et al. 2004; Gianetti et al. 2012; Benduzzi et al. 2012; Abel et al. 2013; Benduzzi et al. 2014). The p.[Asn10Lys;Gln11Lys] complex allele has also been reported in a heterozygous state in at least four unaffected family members (Meysing et al. 2004; Gianetti et al. 2012; Benduzzi et al. 2012). The c.31C>A (p.Gln11Lys) variant has also been reported in two individuals who also carry two other missense variants whose genotype was not provided (Sykiotis et al. 2010; Miraoui et al. 2013). The p.Asn10Lys variant has also been reported in one study in which it was found in a compound heterozygous state with the p.Gln11Lys variant in two individuals (Gurbuz et al. 2012). The complex allele has been reported to be absent from 552 controls (Gianetti et al. 2012; Benduzzi et al. 2012), and each individual variant of the complex allele is reported at a frequency of 0.00029 in the European (Non-Finnish) population of the Exome Aggregation Consortium. Functional studies in COS-7 cells demonstrated that the p.[Asn10Lys;Gln11Lys] allele resulted in reduced cell surface expression, reduced efficacy of coupling of GnRHR to intracellular signaling pathways, and significantly reduced ligand binding (Meysing et al. 2004). The presence of a double allele complicates the classification of any individual variant. Based on the evidence, the p.[Asn10Lys;Gln11Lys] allele is classified as likely pathogenic for isolated GnRH deficiency while the single c.31C>A (p.Gln11Lys) variant when found alone is classified as a variant of unknown significance for isolated GnRH deficiency. -

Hypogonadotropic hypogonadism 7 with or without anosmia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.090

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.25

T;.

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.45

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.70

T;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.32

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.2

L;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.32

N;N

REVEL

Uncertain

0.40

Sift

Benign

0.52

T;T

Sift4G

Benign

0.93

T;T

Polyphen

0.0010

B;B

Vest4

0.74

MVP

0.83

MPC

0.064

ClinPred

0.84

GERP RS

5.2

Varity_R

0.11

gMVP

0.56

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