8-25421627-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001083111.2(GNRH1):c.183C>T(p.Phe61=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00643 in 1,606,116 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (29 hom., cov: 31)
  • Exomes 𝑓: 0.0058 (57 hom.)
• Consequence: GNRH1 NM_001083111.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.82

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 8-25421627-G-A is Benign according to our data. Variant chr8-25421627-G-A is described in ClinVar as [Benign]. Clinvar id is 788272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.82 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0129 (1960/152196) while in subpopulation AFR AF= 0.0343 (1424/41504). AF 95% confidence interval is 0.0328. There are 29 homozygotes in gnomad4. There are 933 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 29 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNRH1	NM_001083111.2	c.183C>T	p.Phe61=	synonymous_variant	3/4	ENST00000421054.7
GNRH1	NM_000825.3	c.195C>T	p.Phe65=	synonymous_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNRH1	ENST00000421054.7	c.183C>T	p.Phe61=	synonymous_variant	3/4	1	NM_001083111.2	P1
GNRH1	ENST00000276414.4	c.183C>T	p.Phe61=	synonymous_variant	2/3	1		P1

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1943 AN: 152078 Hom.: 29 Cov.: 31

Gnomad AFR AF: 0.0340

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00806

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00528

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.00524 AC: 1304 AN: 248810 Hom.: 11 AF XY: 0.00477 AC XY: 644 AN XY: 135016

Gnomad AFR exome AF: 0.0358

Gnomad AMR exome AF: 0.00395

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000295

Gnomad FIN exome AF: 0.00269

Gnomad NFE exome AF: 0.00462

Gnomad OTH exome AF: 0.00415

GnomAD4 exome AF: 0.00575 AC: 8366 AN: 1453920 Hom.: 57 Cov.: 27 AF XY: 0.00555 AC XY: 4014 AN XY: 723754

Gnomad4 AFR exome AF: 0.0397

Gnomad4 AMR exome AF: 0.00430

Gnomad4 ASJ exome AF: 0.000192

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00296

Gnomad4 NFE exome AF: 0.00573

Gnomad4 OTH exome AF: 0.00539

GnomAD4 genome AF: 0.0129 AC: 1960 AN: 152196 Hom.: 29 Cov.: 31 AF XY: 0.0125 AC XY: 933 AN XY: 74418

Gnomad4 AFR AF: 0.0343

Gnomad4 AMR AF: 0.00798

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00528

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.00824 Hom.: 4

Bravo AF: 0.0141

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.00458

EpiControl AF: 0.00427

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 22, 2023

- -

Hypogonadotropic hypogonadism 12 with or without anosmia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.091
Dann	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6186; hg19: chr8-25279143; COSMIC: COSV52382378; COSMIC: COSV52382378;