chr4-67754306-A-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_StrongBP4

The NM_000406.3(GNRHR):c.30T>A(p.Asn10Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000127 in 1,611,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

GNRHR
NM_000406.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 1.13

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 Likely_pathogenic. Variant got 7 ACMG points.

PP5

Variant 4-67754306-A-T is Pathogenic according to our data. Variant chr4-67754306-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.15855774). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNRHR	NM_000406.3 link	c.30T>A	p.Asn10Lys	missense_variant	Exon 1 of 3	ENST00000226413.5	NP_000397.1	P30968-1
GNRHR	NM_001012763.2 link	c.30T>A	p.Asn10Lys	missense_variant	Exon 1 of 3		NP_001012781.1	P30968-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNRHR	ENST00000226413.5 link	c.30T>A	p.Asn10Lys	missense_variant	Exon 1 of 3	1	NM_000406.3	ENSP00000226413.5		P30968-1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152138

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:

0.000478

GnomAD3 exomes

AF:

0.000129

AC:

AN:

247756

Hom.:

AF XY:

0.000156

AC XY:

AN XY:

134566

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:

195

AN:

1459674

Hom.:

Cov.:

AF XY:

0.000138

AC XY:

100

AN XY:

726244

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:

0.0000387

Gnomad4 NFE exome

AF:

0.000162

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74434

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:

0.000473

Alfa

AF:

0.0000961

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.000173

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000474

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypogonadotropic hypogonadism 7 with or without anosmia

Pathogenic:3

Mar 29, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 14, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GNRHR c.30T>A (p.Asn10Lys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 247756 control chromosomes (i.e., 32 heterozygotes and no homozygotes; gnomAD v2.1 Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.30T>A has been reported in the literature in individuals at least four compound heterozygous siblings from a single family with partial hypogonadotropic hypogonadism (e.g., Costa_2001), and the variant was shown to segregate with disease. These data indicate that the variant is likely to be associated with disease. Additionally, the variant of interest has also been identified in cis with p.Gln11Lys in at least two compound heterozygous patients affected with hypogonadotropic hypogonadism (in trans with p.Pro320Leu, PMIDs: 15240592, 22745237, 20696889, 23643382; in trans with p.Tyr283His, PMID: 31200363) and in another heterozygous patient that also harbored WDR11 variant p.Arg448Trp (PMID: 29419413). At least two publications report experimental evidence evaluating an impact on protein function, finding that the variant leads to a two-fold reduction in ligand binding affinity in vitro (e.g., Costa_2001, Leanos-Miranda_2002). The following publications have been ascertained in the context of this evaluation (PMID: 11397871, 12364481, 20696889). One submitter has reported clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Isolated GnRH Deficiency

Pathogenic:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.30T>A (p.Asn10Lys) variant has been reported as part of a complex allele with the c.31C>A (p.Gln11Lys) 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 signalling 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.30T>A (p.Asn10Lys) variant when found alone is classified as a variant of unknown significance for isolated GnRH deficiency. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.37

T;.

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.57

T;T

M_CAP

Benign

0.025

MetaRNN

Benign

0.16

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.6

L;L

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.5

N;N

REVEL

Benign

0.13

Sift

Benign

0.34

T;T

Sift4G

Benign

0.98

T;T

Polyphen

0.0

B;B

Vest4

0.73

MutPred

0.68

Gain of methylation at N10 (P = 0.0011);Gain of methylation at N10 (P = 0.0011);

MVP

0.83

MPC

0.059

ClinPred

0.69

GERP RS

0.97

Varity_R

0.095

gMVP

0.39

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