4-67753832-A-T

Position:

• chr4-67753832-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

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. 13/21 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, single submitter P:2 U:1
• Conservation: PhyloP100: -0.349

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

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 id is 16028.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNRHR	NM_000406.3	c.504T>A	p.Ser168Arg	missense_variant	1/3	ENST00000226413.5	NP_000397.1
GNRHR	NM_001012763.2	c.504T>A	p.Ser168Arg	missense_variant	1/3		NP_001012781.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNRHR	ENST00000226413.5	c.504T>A	p.Ser168Arg	missense_variant	1/3	1	NM_000406.3	ENSP00000226413	P1
UBA6-DT	ENST00000500538.7	n.1921-1357A>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypogonadotropic hypogonadism 7 with or without anosmia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 13, 2024	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1999	- -

Amenorrhea Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Mar 08, 2021

- -

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
MutationTaster	Benign	4.3e-10	A;A
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

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

LitVar

Other links and lift over

dbSNP: rs104893840; hg19: chr4-68619550;