rs104893840

Variant names:

• chr4-67753832-A-T
• rs104893840
• NM_000406.3:c.504T>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000406.3(GNRHR):​c.504T>A​(p.Ser168Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNRHR NM_000406.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1
• Conservation: PhyloP100: -0.349
• Publications: 22 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 17 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 0 uncertain in NM_000406.3
• PM2: Very rare variant in population databases, with high coverage
• 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: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 4-67753832-A-T is Pathogenic according to our data. Variant chr4-67753832-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 16028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNRHR	NM_000406.3	c.504T>A	p.Ser168Arg	missense_variant	Exon 1 of 3	ENST00000226413.5	NP_000397.1
GNRHR	NM_001012763.2	c.504T>A	p.Ser168Arg	missense_variant	Exon 1 of 3		NP_001012781.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNRHR	ENST00000226413.5	c.504T>A	p.Ser168Arg	missense_variant	Exon 1 of 3	1	NM_000406.3	ENSP00000226413.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypogonadotropic hypogonadism 7 with or without anosmia Pathogenic:3

Jun 17, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 13, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GNRHR c.504T>A (p.Ser168Arg) results in a non-conservative amino acid change located in the GPCR, rhodopsin-like, 7TM domain (IPR017452) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250040 control chromosomes. c.504T>A has been reported in the literature in multiple homozygous individuals affected with Hypogonadotropic Hypogonadism 7 With Or Without Anosmia (e.g. Leanos-Miranda_2002, Fathi_2012, Pralong_1999). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in loss of receptor function in transfected COS-7 cells (Pralong_1999). The following publications have been ascertained in the context of this evaluation (PMID: 23155690, 12364481, 10523035). ClinVar contains an entry for this variant (Variation ID: 16028). Based on the evidence outlined above, the variant was classified as pathogenic. -

Oct 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Amenorrhea Uncertain:1

Mar 08, 2021

Yale Center for Mendelian Genomics, Yale University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.0056	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Uncertain	0.57	D;.
Eigen	Benign	-0.93
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.013	T
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;N
PhyloP100		-0.35
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.27
Sift	Benign	0.18	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.60	P;P
Vest4		0.78
MutPred		0.89		Gain of MoRF binding (P = 0.0198);Gain of MoRF binding (P = 0.0198);
MVP		0.37
MPC		0.13
ClinPred		0.18	T
GERP RS		-1.2
Varity_R		0.25
gMVP		0.73
Mutation Taster		=44/56	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: rs104893840; hg19: chr4-68619550;