4-67747463-T-C

Position:

• chr4-67747463-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000406.3(GNRHR):​c.523-2676A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 151,988 control chromosomes in the GnomAD database, including 5,670 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 0.27 (5670 hom., cov: 32)
  • Exomes 𝑓: 0.23 (0 hom.)
• Consequence: GNRHR NM_000406.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.24

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.278 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNRHR	NM_000406.3	c.523-2676A>G		intron_variant		ENST00000226413.5	NP_000397.1
GNRHR	NM_001012763.2	c.523-2804A>G		intron_variant			NP_001012781.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNRHR	ENST00000226413.5	c.523-2676A>G		intron_variant		1	NM_000406.3	ENSP00000226413	P1
UBA6-DT	ENST00000500538.7	n.1921-7726T>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.269 AC: 40852 AN: 151848 Hom.: 5656 Cov.: 32

Gnomad AFR AF: 0.276

Gnomad AMI AF: 0.441

Gnomad AMR AF: 0.264

Gnomad ASJ AF: 0.244

Gnomad EAS AF: 0.184

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.282

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.281

Gnomad OTH AF: 0.255

GnomAD4 exome AF: 0.227 AC: 5 AN: 22 Hom.: 0 AF XY: 0.125 AC XY: 2 AN XY: 16

Gnomad4 FIN exome AF: 0.250

Gnomad4 NFE exome AF: 0.214

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.269 AC: 40888 AN: 151966 Hom.: 5670 Cov.: 32 AF XY: 0.265 AC XY: 19709 AN XY: 74284

Gnomad4 AFR AF: 0.277

Gnomad4 AMR AF: 0.264

Gnomad4 ASJ AF: 0.244

Gnomad4 EAS AF: 0.183

Gnomad4 SAS AF: 0.102

Gnomad4 FIN AF: 0.282

Gnomad4 NFE AF: 0.281

Gnomad4 OTH AF: 0.252

Alfa AF: 0.270 Hom.: 705

Bravo AF: 0.277

Asia WGS AF: 0.156 AC: 545 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.25
DANN	Benign	0.41

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: rs3796718; hg19: chr4-68613181;