4-67754305-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PP2PP5BP4

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. 14/22 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

Publications

13 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000406.3

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 24 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 0.30095 (below the threshold of 3.09). Trascript score misZ: 0.14426 (below the threshold of 3.09). GenCC associations: The gene is linked to hypogonadotropic hypogonadism 7 with or without anosmia, hypogonadotropic hypogonadism.

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 VariationId is 349458.

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 rank	MANE	Protein	UniProt
GNRHR	NM_000406.3 link	c.31C>A	p.Gln11Lys	missense_variant	Exon 1 of 3	ENST00000226413.5	NP_000397.1	P30968-1
GNRHR	NM_001012763.2 link	c.31C>A	p.Gln11Lys	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.31C>A	p.Gln11Lys	missense_variant	Exon 1 of 3	1	NM_000406.3	ENSP00000226413.5		P30968-1

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

GnomAD2 exomes

AF:

0.000129

AC:

AN:

247808

AF XY:

0.000156

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 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

African (AFR)

AF:

0.0000896

AC:

AN:

33470

American (AMR)

AF:

0.0000671

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.0000580

AC:

AN:

51694

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000162

AC:

180

AN:

1111538

Other (OTH)

AF:

0.0000828

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41572

American (AMR)

AF:

0.00

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68024

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000265

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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Mar 29, 2024

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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

PhyloP100

2.4

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

PromoterAI

-0.0020

Neutral

(source)

Varity_R

0.11

gMVP

0.56

Mutation Taster

=12/88

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over