Genetic Variant NM_000406.3:c.785G>A (chr4-67740682-C-T) – ACMG Classification: Pathogenic (16 pts)

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 18P and 2B. PS3PM1PM5PP2PP3PP5_Very_StrongBP4BS2_Supporting

The NM_000406.3(GNRHR):c.785G>A(p.Arg262Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,604,490 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000916073: Functional evaluation of receptor stimulation by ligand induced signaling stimulation of p.Arg262Gln variant GnRHR resulted in significantly less phospholipase C activity compared to wild type GnRHR, demonstrating p.Arg262Gln is functionally deficient (Bedecarrats et al. 2003)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R262W) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 7 hom. )

Consequence

GNRHR
NM_000406.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18U:1

Conservation

PhyloP100: 7.80

Publications

72 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: Pathogenic. The variant received 16 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000916073: Functional evaluation of receptor stimulation by ligand induced signaling stimulation of p.Arg262Gln variant GnRHR resulted in significantly less phospholipase C activity compared to wild type GnRHR, demonstrating p.Arg262Gln is functionally deficient (Bedecarrats et al. 2003).; SCV001142337: Functional evaluation of receptor stimulation by ligand induced signaling stimulation of p.Arg262Gln variant GnRHR resulted in significantly less phospholipase C activity compared to wild type GnRHR, demonstrating p.Arg262Gln is functionally deficient (PMID: 12574221).; SCV002767943: "Functional studies on this variant showed a decrease in phospholipase C activity compared to wild type, resulting in a partial loss of function." PMID:9371856, PMID:12574221; SCV000583021: Published functional studies demonstrate a damaging effect on IP3 production and GnRH signal transmission (de Roux et al., 1997; Layman et al., 1998); PMID: 9371856, 24732674, 16968799, 22745237, 26207952, 23643382, 22788855, 15728205, 12364481, 19820032, 12574221, 17235395, 23155690, 9425890, 21247312, 20696889, 27884859, 26572316, 17074994, 27899157, 12477532, 29419413, 28611058, 29182666, 30476149, 31200363, 31980526, 32870266, 34198905, 34426522, 10690855, 31589614, 11384641; SCV002209386: Experimental studies have shown that this missense change affects GNRHR function (PMID: 9371856, 9425890, 12574221).

PM1

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

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-67740683-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2151986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.

PP3

Multiple lines of computational evidence support a deleterious effect 8: BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, phyloP100way_vertebrate, REVEL, REVEL [when AlphaMissense, BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

PP5

Variant 4-67740682-C-T is Pathogenic according to our data. Variant chr4-67740682-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 16024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.07624191). . Strength limited to SUPPORTING due to the PP5.

BS2

High Homozygotes in GnomAdExome4 at 7 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000406.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNRHR	NM_000406.3	MANE Select	c.785G>A	p.Arg262Gln	missense	Exon 3 of 3	NP_000397.1	P30968-1
	GNRHR	NM_001012763.2		c.657G>A	p.Thr219Thr	synonymous	Exon 3 of 3	NP_001012781.1	P30968-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GNRHR	ENST00000226413.5	TSL:1 MANE Select	c.785G>A	p.Arg262Gln	missense	Exon 3 of 3	ENSP00000226413.5	P30968-1
GNRHR	ENST00000420975.2	TSL:1	c.657G>A	p.Thr219Thr	synonymous	Exon 3 of 3	ENSP00000397561.2	P30968-2
UBA6-DT	ENST00000500538.7	TSL:1	n.1920+8337C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00130

AC:

198

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00473

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00181

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.00179

AC:

448

AN:

250854

AF XY:

0.00171

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00531

Gnomad NFE exome

AF:

0.00215

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00155

AC:

2258

AN:

1452324

Hom.:

Cov.:

AF XY:

0.00155

AC XY:

1123

AN XY:

723254

show subpopulations

African (AFR)

AF:

0.0000901

AC:

AN:

33284

American (AMR)

AF:

0.000268

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26070

East Asian (EAS)

AF:

0.00

AC:

AN:

39632

South Asian (SAS)

AF:

0.00214

AC:

184

AN:

86074

European-Finnish (FIN)

AF:

0.00605

AC:

323

AN:

53418

Middle Eastern (MID)

AF:

0.000522

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00150

AC:

1653

AN:

1103314

Other (OTH)

AF:

0.00128

AC:

AN:

60072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

109

218

326

435

544

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<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:

0.00130

AC:

198

AN:

152166

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

103

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41530

American (AMR)

AF:

0.000262

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00145

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00473

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00181

AC:

123

AN:

67994

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

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:

0.00168

Hom.:

Bravo

AF:

0.00107

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00221

AC:

ExAC

AF:

0.00203

AC:

247

Asia WGS

AF:

0.000578

AC:

AN:

3476

EpiCase

AF:

0.00136

EpiControl

AF:

0.00136

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypogonadotropic hypogonadism 7 with or without anosmia (12)

not provided (2)

Pituitary hormone deficiency (2)

Amenorrhea (1)

Hypogonadotropic hypogonadism (1)

See cases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

0.0071

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.75

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.41

MetaRNN

Benign

0.076

MetaSVM

Uncertain

0.19

PhyloP100

7.8

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.5

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.93

MVP

0.89

MPC

0.34

ClinPred

0.087

GERP RS

5.4

Varity_R

0.73

gMVP

0.71

Mutation Taster

=3/97

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over