4-67737984-C-T

Position:

• chr4-67737984-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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. Variant has been reported in ClinVar as Benign (★).

• 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

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 4-67737984-C-T is Benign according to our data. Variant chr4-67737984-C-T is described in ClinVar as [Benign]. Clinvar id is 349421.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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/exons	MANE	Protein	UniProt
GNRHR	NM_000406.3	c.*2496G>A		3_prime_UTR_variant	3/3	ENST00000226413.5	NP_000397.1
GNRHR	NM_001012763.2	c.*2605G>A		3_prime_UTR_variant	3/3		NP_001012781.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNRHR	ENST00000226413.5	c.*2496G>A		3_prime_UTR_variant	3/3	1	NM_000406.3	ENSP00000226413	P1
UBA6-DT	ENST00000500538.7	n.1920+5639C>T		intron_variant, non_coding_transcript_variant		1

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

Gnomad4 AFR AF: 0.380

Gnomad4 AMR AF: 0.362

Gnomad4 ASJ AF: 0.427

Gnomad4 EAS AF: 0.323

Gnomad4 SAS AF: 0.325

Gnomad4 FIN AF: 0.394

Gnomad4 NFE AF: 0.398

Gnomad4 OTH AF: 0.379

Alfa AF: 0.401 Hom.: 10691

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1038427; hg19: chr4-68603702;