NM_001083111.2:c.47G>C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001083111.2(GNRH1):​c.47G>C​(p.Trp16Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 1,609,944 control chromosomes in the GnomAD database, including 50,204 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3916 hom., cov: 32)
  • Exomes 𝑓: 0.24 (46288 hom.)
• Consequence: GNRH1 NM_001083111.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.604127E-4).
• BP6: Variant 8-25423284-C-G is Benign according to our data. Variant chr8-25423284-C-G is described in ClinVar as Benign. ClinVar VariationId is 362652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.534 is higher than 0.05.

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>C	p.Trp16Ser	missense	Exon 2 of 4	NP_001076580.1	P01148
	GNRH1	NM_000825.3		c.59G>C	p.Trp20Ser	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>C	p.Trp16Ser	missense	Exon 2 of 4	ENSP00000391280.2	P01148
	GNRH1	ENST00000276414.4	TSL:1	c.47G>C	p.Trp16Ser	missense	Exon 1 of 3	ENSP00000276414.4	P01148
	GNRH1	ENST00000966630.1		c.47G>C	p.Trp16Ser	missense	Exon 2 of 4	ENSP00000636689.1

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31261 AN: 152034 Hom.: 3918 Cov.: 32

Gnomad AFR AF: 0.0830

Gnomad AMI AF: 0.242

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.551

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.276

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.250

Gnomad OTH AF: 0.216

GnomAD2 exomes AF: 0.232 AC: 57704 AN: 249258 AF XY: 0.229

Gnomad AFR exome AF: 0.0837

Gnomad AMR exome AF: 0.140

Gnomad ASJ exome AF: 0.265

Gnomad EAS exome AF: 0.543

Gnomad FIN exome AF: 0.277

Gnomad NFE exome AF: 0.248

Gnomad OTH exome AF: 0.231

GnomAD4 exome AF: 0.242 AC: 352936 AN: 1457792 Hom.: 46288 Cov.: 30 AF XY: 0.239 AC XY: 173556 AN XY: 725464

African (AFR) AF: 0.0767 AC: 2565 AN: 33422

American (AMR) AF: 0.146 AC: 6521 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 7026 AN: 26100

East Asian (EAS) AF: 0.528 AC: 20954 AN: 39670

South Asian (SAS) AF: 0.124 AC: 10689 AN: 86198

European-Finnish (FIN) AF: 0.278 AC: 14854 AN: 53408

Middle Eastern (MID) AF: 0.176 AC: 1014 AN: 5760

European-Non Finnish (NFE) AF: 0.248 AC: 274820 AN: 1108288

Other (OTH) AF: 0.241 AC: 14493 AN: 60244

GnomAD4 genome AF: 0.205 AC: 31240 AN: 152152 Hom.: 3916 Cov.: 32 AF XY: 0.207 AC XY: 15375 AN XY: 74370

African (AFR) AF: 0.0829 AC: 3444 AN: 41558

American (AMR) AF: 0.184 AC: 2812 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 913 AN: 3468

East Asian (EAS) AF: 0.550 AC: 2840 AN: 5160

South Asian (SAS) AF: 0.122 AC: 587 AN: 4824

European-Finnish (FIN) AF: 0.276 AC: 2925 AN: 10586

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.250 AC: 16984 AN: 67968

Other (OTH) AF: 0.216 AC: 455 AN: 2110

Alfa AF: 0.250 Hom.: 3860

Bravo AF: 0.198

TwinsUK AF: 0.253 AC: 939

ALSPAC AF: 0.256 AC: 985

ESP6500AA AF: 0.0924 AC: 348

ESP6500EA AF: 0.251 AC: 2064

ExAC AF: 0.233 AC: 28150

Asia WGS AF: 0.292 AC: 1012 AN: 3478

EpiCase AF: 0.254

EpiControl AF: 0.239

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Hypogonadotropic hypogonadism 12 with or without anosmia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	15
DANN	Benign	0.58
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.00026	T
MetaSVM	Benign	-0.92	T
PhyloP100		3.4
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.18	N
REVEL	Benign	0.092
Sift	Benign	0.093	T
Sift4G	Benign	0.43	T
Polyphen		0.0020	B
Vest4		0.11
MPC		0.31
ClinPred		0.013	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.093
gMVP		0.34
Mutation Taster		=96/4	polymorphism (auto)

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: rs6185; hg19: chr8-25280800; COSMIC: COSV52381938; COSMIC: COSV52381938;