chr8-25422909-T-C

Position:

• chr8-25422909-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001083111.2(GNRH1):​c.141+281A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0193 in 152,340 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.019 (38 hom., cov: 32)
• Consequence: GNRH1 NM_001083111.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.587

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 8-25422909-T-C is Benign according to our data. Variant chr8-25422909-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1185918.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0193 (2943/152340) while in subpopulation NFE AF= 0.0309 (2104/68018). AF 95% confidence interval is 0.0298. There are 38 homozygotes in gnomad4. There are 1353 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 38 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNRH1	NM_001083111.2	c.141+281A>G		intron_variant		ENST00000421054.7	NP_001076580.1
GNRH1	NM_000825.3	c.153+281A>G		intron_variant			NP_000816.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNRH1	ENST00000421054.7	c.141+281A>G		intron_variant		1	NM_001083111.2	ENSP00000391280.2
GNRH1	ENST00000276414.4	c.141+281A>G		intron_variant		1		ENSP00000276414.4

Frequencies

GnomAD3 genomes AF: 0.0193 AC: 2944 AN: 152222 Hom.: 38 Cov.: 32

Gnomad AFR AF: 0.00610

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0209

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.0135

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0309

Gnomad OTH AF: 0.0182

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

GnomAD4 genome AF: 0.0193 AC: 2943 AN: 152340 Hom.: 38 Cov.: 32 AF XY: 0.0182 AC XY: 1353 AN XY: 74492

Gnomad4 AFR AF: 0.00608

Gnomad4 AMR AF: 0.0209

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.0135

Gnomad4 NFE AF: 0.0309

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.0262 Hom.: 14

Bravo AF: 0.0186

Asia WGS AF: 0.00404 AC: 15 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 14, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.54
DANN	Benign	0.44

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: rs76986108; hg19: chr8-25280425;