NM_001083111.2:c.87delA

Variant names:

• chr8-25423243-GT-G
• rs587777859
• NM_001083111.2:c.87delA

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PP5_Moderate

The NM_001083111.2(GNRH1):​c.87delA​(p.Leu30CysfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000219 in 1,460,040 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: GNRH1 NM_001083111.2 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: -1.35
• Publications: 4 publications found

Genes affected

GNRH1 (HGNC:4419): (gonadotropin releasing hormone 1) This gene encodes a preproprotein that is proteolytically processed to generate a peptide that is a member of the gonadotropin-releasing hormone (GnRH) family of peptides. Alternative splicing results in multiple transcript variants, at least one of which is secreted and then cleaved to generate gonadoliberin-1 and GnRH-associated peptide 1. Gonadoliberin-1 stimulates the release of luteinizing and follicle stimulating hormones, which are important for reproduction. Mutations in this gene are associated with hypogonadotropic hypogonadism. [provided by RefSeq, Nov 2015]

GNRH1 Gene-Disease associations (from GenCC):

• hypogonadotropic hypogonadism 12 with or without anosmia

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hypogonadotropic hypogonadism

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.688 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PP5: Variant 8-25423243-GT-G is Pathogenic according to our data. Variant chr8-25423243-GT-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 156555.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001083111.2. 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
	GNRH1	NM_001083111.2	MANE Select	c.87delA	p.Leu30CysfsTer12	frameshift	Exon 2 of 4	NP_001076580.1	P01148
	GNRH1	NM_000825.3		c.99delA	p.Leu34CysfsTer12	frameshift	Exon 1 of 3	NP_000816.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNRH1	ENST00000421054.7	TSL:1 MANE Select	c.87delA	p.Leu30CysfsTer12	frameshift	Exon 2 of 4	ENSP00000391280.2	P01148
	GNRH1	ENST00000276414.4	TSL:1	c.87delA	p.Leu30CysfsTer12	frameshift	Exon 1 of 3	ENSP00000276414.4	P01148
	GNRH1	ENST00000966630.1		c.87delA	p.Leu30CysfsTer12	frameshift	Exon 2 of 4	ENSP00000636689.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1460040 Hom.: 0 Cov.: 30 AF XY: 0.0000151 AC XY: 11 AN XY: 726498

African (AFR) AF: 0.00 AC: 0 AN: 33438

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000261 AC: 29 AN: 1110364

Other (OTH) AF: 0.0000497 AC: 3 AN: 60340

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Hypogonadotropic hypogonadism 12 with or without anosmia (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.3
Mutation Taster		=23/177	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs587777859; hg19: chr8-25280759;