4-67738039-A-G

Variant names:

• chr4-67738039-A-G
• rs2319657
• NM_000406.3:c.*2441T>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.*2441T>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 0.0633 in 151,680 control chromosomes in the GnomAD database, including 348 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.063 (348 hom., cov: 32)
• Consequence: GNRHR NM_000406.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.48
• Publications: 2 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=-0.57).
• BP6: Variant 4-67738039-A-G is Benign according to our data. Variant chr4-67738039-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 906358.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0654 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNRHR	NM_000406.3	c.*2441T>C		3_prime_UTR_variant	Exon 3 of 3	ENST00000226413.5	NP_000397.1
GNRHR	NM_001012763.2	c.*2550T>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.*2441T>C		3_prime_UTR_variant	Exon 3 of 3	1	NM_000406.3	ENSP00000226413.5

Frequencies

GnomAD3 genomes AF: 0.0633 AC: 9595 AN: 151566 Hom.: 348 Cov.: 32

Gnomad AFR AF: 0.0624

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0614

Gnomad ASJ AF: 0.0865

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0228

Gnomad FIN AF: 0.0879

Gnomad MID AF: 0.0701

Gnomad NFE AF: 0.0671

Gnomad OTH AF: 0.0784

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

GnomAD4 genome AF: 0.0633 AC: 9597 AN: 151680 Hom.: 348 Cov.: 32 AF XY: 0.0633 AC XY: 4693 AN XY: 74144

African (AFR) AF: 0.0623 AC: 2584 AN: 41496

American (AMR) AF: 0.0614 AC: 934 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.0865 AC: 300 AN: 3468

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5186

South Asian (SAS) AF: 0.0228 AC: 110 AN: 4822

European-Finnish (FIN) AF: 0.0879 AC: 922 AN: 10486

Middle Eastern (MID) AF: 0.0719 AC: 21 AN: 292

European-Non Finnish (NFE) AF: 0.0671 AC: 4541 AN: 67698

Other (OTH) AF: 0.0776 AC: 163 AN: 2100

Alfa AF: 0.0726 Hom.: 56

Bravo AF: 0.0615

Asia WGS AF: 0.0100 AC: 35 AN: 3422

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 13, 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	-0.57
CADD	Benign	7.2
DANN	Benign	0.76
PhyloP100		2.5
Mutation Taster		=99/1	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2319657; hg19: chr4-68603757;