chr4-67754019-T-C

Variant names:

• chr4-67754019-T-C
• rs104893836
• NM_000406.3:c.317A>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 13P and 2B. PS3 PP2 PP5_Very_Strong BP4 BS2_Supporting

The NM_000406.3(GNRHR):​c.317A>G​(p.Gln106Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00354 in 1,613,870 control chromosomes in the GnomAD database, including 10 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: "SCV000916074: "In vitro expression analysis in CHO-K1 and COS-7 cells found p.Gln106Arg to have significantly reduced GNRH binding activity and reduced inositol phosphates binding compared to wildtype." PMID:16332762" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0023 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (8 hom.)
• Consequence: GNRHR NM_000406.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:31 O:1
• Conservation: PhyloP100: 7.95
• Publications: 85 publications found

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]

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

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000916074: "In vitro expression analysis in CHO-K1 and COS-7 cells found p.Gln106Arg to have significantly reduced GNRH binding activity and reduced inositol phosphates binding compared to wildtype." PMID:16332762; SCV001142338: "In vitro functional studies demonstrated that p.Q106R results in a loss of function of the receptor protein." PMID:9371856; SCV002557930: "This variant has moderate functional evidence supporting abnormal protein function. In vitro studies showed decreased binding to its ligand, GNRH (PMID: 9371856, 15728205)."; SCV003934500: Multiple publications have reported experimental evidence that this variant reduced ligand binding (examples: de Roux_1997 and Leanos-Miranda_2002). The following publications have been ascertained in the context of this evaluation (PMID: 12364481, 9371856, 25077900).; SCV000321746: Published functional studies demonstrate a damaging effect by reducing the binding of GnRH-A and decreasing the activation of phospholipase C (de Roux et al., 1997);; SCV000931625: Experimental studies have shown that this missense change affects GNRHR function (PMID: 9371856, 12364481, 12574221, 15728205).; SCV002070515: "In-vitro studies showed the binding of GnRH was reduced in cells transfected with the p.Gln106Arg sequence change." PMID:9371856; SCV004229679: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 9371856, 12364481, 12574221); SCV000245617: In vitro functional assays indicate this variant leads to partial loss of GNRHR function (de Roux 1997 PMID: 9371856, Leanos-Miranda 2002 PMID: 12364481); SCV004107189: "In vitro functional studies have shown the p.Gln106Arg variant results in partial loss of function of the GNRHR receptor protein (de Roux et al. 1997. PubMed ID: 9371856; Leanos-Miranda et al. 2002. PubMed ID: 12364481; Gianetti et al. 2012. PubMed ID: 22745237)."; SCV004878661: In multiple assays testing GNRHR function, this variant has been shown to significantly reduce GnRH binding and decrease PLC activity as measured by decrease in intracellular IP production in response to GnRH (de Roux, 1997; Leanos-Miranda, 2005; Bedecarrats, 2003; Leanos-Miranda, 2002).
• 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 4-67754019-T-C is Pathogenic according to our data. Variant chr4-67754019-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 16023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.02444002). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAd4 at 2 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.317A>G	p.Gln106Arg	missense	Exon 1 of 3	NP_000397.1	P30968-1
	GNRHR	NM_001012763.2		c.317A>G	p.Gln106Arg	missense	Exon 1 of 3	NP_001012781.1	P30968-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNRHR	ENST00000226413.5	TSL:1 MANE Select	c.317A>G	p.Gln106Arg	missense	Exon 1 of 3	ENSP00000226413.5	P30968-1
	GNRHR	ENST00000420975.2	TSL:1	c.317A>G	p.Gln106Arg	missense	Exon 1 of 3	ENSP00000397561.2	P30968-2
	UBA6-DT	ENST00000500538.7	TSL:1	n.1921-1170T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00234 AC: 356 AN: 152184 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00354

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00284 AC: 714 AN: 251236 AF XY: 0.00289

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.00586

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00199

Gnomad NFE exome AF: 0.00418

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00366 AC: 5352 AN: 1461568 Hom.: 8 Cov.: 31 AF XY: 0.00362 AC XY: 2632 AN XY: 727138

African (AFR) AF: 0.000598 AC: 20 AN: 33472

American (AMR) AF: 0.00246 AC: 110 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 158 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.000754 AC: 65 AN: 86254

European-Finnish (FIN) AF: 0.00193 AC: 103 AN: 53420

Middle Eastern (MID) AF: 0.00537 AC: 31 AN: 5768

European-Non Finnish (NFE) AF: 0.00422 AC: 4686 AN: 1111714

Other (OTH) AF: 0.00293 AC: 177 AN: 60388

GnomAD4 genome AF: 0.00234 AC: 356 AN: 152302 Hom.: 2 Cov.: 32 AF XY: 0.00216 AC XY: 161 AN XY: 74474

African (AFR) AF: 0.000529 AC: 22 AN: 41570

American (AMR) AF: 0.00288 AC: 44 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00354 AC: 241 AN: 68014

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00348 Hom.: 4

Bravo AF: 0.00238

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00252 AC: 306

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00404

EpiControl AF: 0.00486

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
15	-	-	Hypogonadotropic hypogonadism 7 with or without anosmia (15)
9	-	-	not provided (9)
1	-	-	GNRHR-related disorder (1)
1	-	-	Gonadotropin deficiency (1)
1	-	-	Hypogonadotropic hypogonadism (2)
1	-	-	Inborn genetic diseases (1)
1	-	-	Infertility disorder (1)
1	-	-	Isolated congenital hypogonadotropic hypogonadism (1)
1	-	-	Pituitary hormone deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	0.0096	T
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.3	L
PhyloP100		7.9
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.059	T
Polyphen		1.0	D
Vest4		0.87
MVP		0.87
MPC		0.35
ClinPred		0.052	T
GERP RS		6.2
PromoterAI		0.025	Neutral
Varity_R		0.78
gMVP		0.65
Mutation Taster		=17/83	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104893836; hg19: chr4-68619737;