8-25423284-C-A

Variant names:

• chr8-25423284-C-A
• rs6185
• NM_001083111.2:c.47G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001083111.2(GNRH1):​c.47G>T​(p.Trp16Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W16S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GNRH1 NM_001083111.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.36
• Publications: 51 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_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05749449).

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.47G>T	p.Trp16Leu	missense	Exon 2 of 4	NP_001076580.1	P01148
	GNRH1	NM_000825.3		c.59G>T	p.Trp20Leu	missense	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.47G>T	p.Trp16Leu	missense	Exon 2 of 4	ENSP00000391280.2	P01148
	GNRH1	ENST00000276414.4	TSL:1	c.47G>T	p.Trp16Leu	missense	Exon 1 of 3	ENSP00000276414.4	P01148
	GNRH1	ENST00000966630.1		c.47G>T	p.Trp16Leu	missense	Exon 2 of 4	ENSP00000636689.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249258 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459226 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726102

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109620

Other (OTH) AF: 0.00 AC: 0 AN: 60294

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.030
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	3.2
DANN	Benign	0.50
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.00058	N
LIST_S2	Benign	0.15	T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-0.99	T
PhyloP100		3.4
PrimateAI	Benign	0.27	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.11
Sift	Benign	1.0	T
Sift4G	Benign	0.95	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.36		Loss of catalytic residue at L14 (P = 0.0054)
MVP		0.18
MPC		0.34
ClinPred		0.028	T
GERP RS		2.9
Varity_R		0.053
gMVP		0.14
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs6185; hg19: chr8-25280800; COSMIC: COSV52382557; COSMIC: COSV52382557;