4-67737713-A-G

Variant names:

• chr4-67737713-A-G
• rs12507392
• NM_000406.3:c.*2767T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000406.3(GNRHR):​c.*2767T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0194 in 151,982 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.019 (73 hom., cov: 32)
• Consequence: GNRHR NM_000406.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.294
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 4-67737713-A-G is Benign according to our data. Variant chr4-67737713-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 906355.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNRHR	NM_000406.3	c.*2767T>C		3_prime_UTR_variant	Exon 3 of 3	ENST00000226413.5	NP_000397.1
GNRHR	NM_001012763.2	c.*2876T>C		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.*2767T>C		3_prime_UTR_variant	Exon 3 of 3	1	NM_000406.3	ENSP00000226413.5

Frequencies

GnomAD3 genomes AF: 0.0194 AC: 2948 AN: 151866 Hom.: 75 Cov.: 32

Gnomad AFR AF: 0.00440

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.0440

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.106

Gnomad SAS AF: 0.0166

Gnomad FIN AF: 0.0213

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0157

Gnomad OTH AF: 0.0202

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

GnomAD4 genome AF: 0.0194 AC: 2941 AN: 151982 Hom.: 73 Cov.: 32 AF XY: 0.0201 AC XY: 1495 AN XY: 74306

African (AFR) AF: 0.00443 AC: 184 AN: 41518

American (AMR) AF: 0.0438 AC: 668 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.0173 AC: 60 AN: 3468

East Asian (EAS) AF: 0.105 AC: 543 AN: 5182

South Asian (SAS) AF: 0.0166 AC: 80 AN: 4822

European-Finnish (FIN) AF: 0.0213 AC: 226 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0157 AC: 1064 AN: 67832

Other (OTH) AF: 0.0199 AC: 42 AN: 2106

Alfa AF: 0.0158 Hom.: 7

Bravo AF: 0.0226

Asia WGS AF: 0.0500 AC: 174 AN: 3468

ClinVar

Significance: Likely 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: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.3
DANN	Benign	0.70
PhyloP100		0.29
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs12507392; hg19: chr4-68603431;