8-25421633-T-C

Position:

• chr8-25421633-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_001083111.2(GNRH1):​c.177A>G​(p.Gln59Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000672 in 1,605,268 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00071 (2 hom.)
• Consequence: GNRH1 NM_001083111.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.840

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 8-25421633-T-C is Benign according to our data. Variant chr8-25421633-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 362651.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-0.84 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNRH1	NM_001083111.2	c.177A>G	p.Gln59Gln	synonymous_variant	3/4	ENST00000421054.7	NP_001076580.1
GNRH1	NM_000825.3	c.189A>G	p.Gln63Gln	synonymous_variant	2/3		NP_000816.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNRH1	ENST00000421054.7	c.177A>G	p.Gln59Gln	synonymous_variant	3/4	1	NM_001083111.2	ENSP00000391280.2
GNRH1	ENST00000276414.4	c.177A>G	p.Gln59Gln	synonymous_variant	2/3	1		ENSP00000276414.4

Frequencies

GnomAD3 genomes AF: 0.000303 AC: 46 AN: 152034 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000390 AC: 97 AN: 248856 Hom.: 1 AF XY: 0.000430 AC XY: 58 AN XY: 135026

Gnomad AFR exome AF: 0.0000647

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000589

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000674

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000710 AC: 1032 AN: 1453234 Hom.: 2 Cov.: 28 AF XY: 0.000683 AC XY: 494 AN XY: 723424

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000349

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000858

Gnomad4 OTH exome AF: 0.000667

GnomAD4 genome AF: 0.000303 AC: 46 AN: 152034 Hom.: 0 Cov.: 31 AF XY: 0.000256 AC XY: 19 AN XY: 74272

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000491 Hom.: 0

Bravo AF: 0.000359

EpiCase AF: 0.000600

EpiControl AF: 0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypogonadotropic hypogonadism 12 with or without anosmia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 04, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.35
DANN	Benign	0.23
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs368837931; hg19: chr8-25279149;