4-67752473-A-T

Position:

• chr4-67752473-A-T

Variant summary

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

The NM_000406.3(GNRHR):​c.522+1341T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.481 in 151,518 control chromosomes in the GnomAD database, including 18,091 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 0.48 (18091 hom., cov: 30)
• Consequence: GNRHR NM_000406.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.631

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=-0.97).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.536 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNRHR	NM_000406.3	c.522+1341T>A		intron_variant		ENST00000226413.5
GNRHR	NM_001012763.2	c.522+1341T>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNRHR	ENST00000226413.5	c.522+1341T>A		intron_variant		1	NM_000406.3	P1
UBA6-DT	ENST00000500538.7	n.1921-2716A>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.481 AC: 72874 AN: 151398 Hom.: 18079 Cov.: 30

Gnomad AFR AF: 0.397

Gnomad AMI AF: 0.680

Gnomad AMR AF: 0.443

Gnomad ASJ AF: 0.572

Gnomad EAS AF: 0.316

Gnomad SAS AF: 0.423

Gnomad FIN AF: 0.533

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.541

Gnomad OTH AF: 0.508

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

GnomAD4 genome AF: 0.481 AC: 72906 AN: 151518 Hom.: 18091 Cov.: 30 AF XY: 0.478 AC XY: 35337 AN XY: 73992

Gnomad4 AFR AF: 0.397

Gnomad4 AMR AF: 0.442

Gnomad4 ASJ AF: 0.572

Gnomad4 EAS AF: 0.316

Gnomad4 SAS AF: 0.422

Gnomad4 FIN AF: 0.533

Gnomad4 NFE AF: 0.541

Gnomad4 OTH AF: 0.503

Alfa AF: 0.348 Hom.: 903

Bravo AF: 0.473

Asia WGS AF: 0.330 AC: 1146 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	2.8
DANN	Benign	0.83

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: rs10031252; hg19: chr4-68618191;