4-67738448-TAAA-TAAAA

Variant names:

• chr4-67738448-T-TA
• rs766610755
• NM_000406.3:c.*2031dupT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000406.3(GNRHR):​c.*2031dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000911 in 143,828 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.00091 (0 hom., cov: 32)
• Consequence: GNRHR NM_000406.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.33
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000406.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNRHR	NM_000406.3	MANE Select	c.*2031dupT		3_prime_UTR	Exon 3 of 3	NP_000397.1	P30968-1
	GNRHR	NM_001012763.2		c.*2140dupT		3_prime_UTR	Exon 3 of 3	NP_001012781.1	P30968-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNRHR	ENST00000226413.5	TSL:1 MANE Select	c.*2031dupT		3_prime_UTR	Exon 3 of 3	ENSP00000226413.5	P30968-1
	UBA6-DT	ENST00000500538.7	TSL:1	n.1920+6115dupA		intron	N/A
	UBA6-DT	ENST00000502758.1	TSL:4	n.202+6115dupA		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000918 AC: 132 AN: 143774 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00175

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000198

Gnomad SAS AF: 0.00240

Gnomad FIN AF: 0.000571

Gnomad MID AF: 0.00323

Gnomad NFE AF: 0.000414

Gnomad OTH AF: 0.000508

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

GnomAD4 genome AF: 0.000911 AC: 131 AN: 143828 Hom.: 0 Cov.: 32 AF XY: 0.00100 AC XY: 70 AN XY: 69806

African (AFR) AF: 0.00175 AC: 69 AN: 39430

American (AMR) AF: 0.00118 AC: 17 AN: 14376

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3340

East Asian (EAS) AF: 0.000199 AC: 1 AN: 5036

South Asian (SAS) AF: 0.00219 AC: 10 AN: 4560

European-Finnish (FIN) AF: 0.000571 AC: 5 AN: 8764

Middle Eastern (MID) AF: 0.00352 AC: 1 AN: 284

European-Non Finnish (NFE) AF: 0.000414 AC: 27 AN: 65154

Other (OTH) AF: 0.000504 AC: 1 AN: 1986

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Isolated GnRH Deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs766610755; hg19: chr4-68604166;