chr4-67753832-A-T

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.

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.504T>A	p.Ser168Arg	missense	Exon 1 of 3	NP_000397.1	P30968-1
	GNRHR	NM_001012763.2		c.504T>A	p.Ser168Arg	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.504T>A	p.Ser168Arg	missense	Exon 1 of 3	ENSP00000226413.5	P30968-1
	GNRHR	ENST00000420975.2	TSL:1	c.504T>A	p.Ser168Arg	missense	Exon 1 of 3	ENSP00000397561.2	P30968-2
	UBA6-DT	ENST00000500538.7	TSL:1	n.1921-1357A>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Hypogonadotropic hypogonadism 7 with or without anosmia (3)
-	1	-	Amenorrhea (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.013	T
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.35
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.27
Sift	Benign	0.18	T
Sift4G	Benign	0.15	T
Polyphen		0.60	P
Vest4		0.78
MutPred		0.89		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;