4-67737984-C-T

Variant names:

• chr4-67737984-C-T
• rs1038427
• NM_000406.3:c.*2496G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000406.3(GNRHR):​c.*2496G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.386 in 150,928 control chromosomes in the GnomAD database, including 11,366 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.39 (11366 hom., cov: 31)
• Consequence: GNRHR NM_000406.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.426
• Publications: 7 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.394 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNRHR	NM_000406.3	c.*2496G>A		3_prime_UTR_variant	Exon 3 of 3	ENST00000226413.5	NP_000397.1
GNRHR	NM_001012763.2	c.*2605G>A		3_prime_UTR_variant	Exon 3 of 3		NP_001012781.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNRHR	ENST00000226413.5	c.*2496G>A		3_prime_UTR_variant	Exon 3 of 3	1	NM_000406.3	ENSP00000226413.5

Frequencies

GnomAD3 genomes AF: 0.386 AC: 58249 AN: 150818 Hom.: 11354 Cov.: 31

Gnomad AFR AF: 0.380

Gnomad AMI AF: 0.602

Gnomad AMR AF: 0.362

Gnomad ASJ AF: 0.427

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.326

Gnomad FIN AF: 0.394

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.398

Gnomad OTH AF: 0.383

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.386 AC: 58293 AN: 150928 Hom.: 11366 Cov.: 31 AF XY: 0.384 AC XY: 28319 AN XY: 73688

African (AFR) AF: 0.380 AC: 15687 AN: 41254

American (AMR) AF: 0.362 AC: 5483 AN: 15144

Ashkenazi Jewish (ASJ) AF: 0.427 AC: 1475 AN: 3452

East Asian (EAS) AF: 0.323 AC: 1662 AN: 5142

South Asian (SAS) AF: 0.325 AC: 1558 AN: 4796

European-Finnish (FIN) AF: 0.394 AC: 4084 AN: 10356

Middle Eastern (MID) AF: 0.528 AC: 149 AN: 282

European-Non Finnish (NFE) AF: 0.398 AC: 26854 AN: 67502

Other (OTH) AF: 0.379 AC: 793 AN: 2090

Alfa AF: 0.400 Hom.: 12265

Bravo AF: 0.388

Asia WGS AF: 0.299 AC: 1025 AN: 3424

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypogonadotropic hypogonadism 7 with or without anosmia Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	3.7
DANN	Benign	0.23
PhyloP100		0.43

Splicing

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

Other links and lift over

dbSNP: rs1038427; hg19: chr4-68603702;