rs104893839

Variant names:

• chr4-67744659-G-T
• rs104893839
• NM_000406.3:c.651C>A
• GNRHR p.Ser217Arg

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP5

The NM_000406.3(GNRHR):​c.651C>A​(p.Ser217Arg) 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 benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNRHR NM_000406.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.98
• Publications: 20 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: Uncertain_significance. The variant received 4 ACMG points.

• 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.
• PP5: Variant 4-67744659-G-T is Pathogenic according to our data. Variant chr4-67744659-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 16027.Status of the report is no_assertion_criteria_provided, 0 stars.

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.651C>A	p.Ser217Arg	missense	Exon 2 of 3	NP_000397.1	P30968-1
	GNRHR	NM_001012763.2		c.523C>A	p.Leu175Met	missense splice_region	Exon 2 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.651C>A	p.Ser217Arg	missense	Exon 2 of 3	ENSP00000226413.5	P30968-1
	GNRHR	ENST00000420975.2	TSL:1	c.523C>A	p.Leu175Met	missense splice_region	Exon 2 of 3	ENSP00000397561.2	P30968-2
	UBA6-DT	ENST00000500538.7	TSL:1	n.1921-10530G>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Hypogonadotropic hypogonadism 7 with or without anosmia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Uncertain	0.060
CADD	Benign	23
DANN	Uncertain	0.99
Eigen	Benign	0.12
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.20	T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.53	T
PhyloP100		2.0
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.17
Sift	Benign	0.13	T
Sift4G	Benign	0.12	T
Varity_R		0.33
Mutation Taster		=26/74	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.29		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs104893839;

hg19: chr4-68610377;