NM_000406.3:c.453C>T

Variant names:

• chr4-67753883-G-A
• rs4986942
• NM_000406.3:c.453C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000406.3(GNRHR):​c.453C>T​(p.Ser151Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0859 in 1,613,558 control chromosomes in the GnomAD database, including 6,507 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.085 (638 hom., cov: 32)
  • Exomes 𝑓: 0.086 (5869 hom.)
• Consequence: GNRHR NM_000406.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.13

Genes affected

GNRHR (HGNC:4421): (gonadotropin releasing hormone receptor) This gene encodes the receptor for type 1 gonadotropin-releasing hormone. This receptor is a member of the seven-transmembrane, G-protein coupled receptor (GPCR) family. It is expressed on the surface of pituitary gonadotrope cells as well as lymphocytes, breast, ovary, and prostate. Following binding of gonadotropin-releasing hormone, the receptor associates with G-proteins that activate a phosphatidylinositol-calcium second messenger system. Activation of the receptor ultimately causes the release of gonadotropic luteinizing hormone (LH) and follicle stimulating hormone (FSH). Defects in this gene are a cause of hypogonadotropic hypogonadism (HH). Alternative splicing results in multiple transcript variants encoding different isoforms. More than 18 transcription initiation sites in the 5' region and multiple polyA signals in the 3' region have been identified for this gene. [provided by RefSeq, Jul 2008]

UBA6-DT (HGNC:49083): (UBA6 divergent transcript)

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 4-67753883-G-A is Benign according to our data. Variant chr4-67753883-G-A is described in ClinVar as [Benign]. Clinvar id is 349456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-67753883-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.13 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNRHR	NM_000406.3	c.453C>T	p.Ser151Ser	synonymous_variant	Exon 1 of 3	ENST00000226413.5	NP_000397.1
GNRHR	NM_001012763.2	c.453C>T	p.Ser151Ser	synonymous_variant	Exon 1 of 3		NP_001012781.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNRHR	ENST00000226413.5	c.453C>T	p.Ser151Ser	synonymous_variant	Exon 1 of 3	1	NM_000406.3	ENSP00000226413.5

Frequencies

GnomAD3 genomes AF: 0.0853 AC: 12979 AN: 152130 Hom.: 636 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.172

Gnomad AMR AF: 0.0875

Gnomad ASJ AF: 0.0879

Gnomad EAS AF: 0.00635

Gnomad SAS AF: 0.0534

Gnomad FIN AF: 0.0282

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0892

Gnomad OTH AF: 0.0823

GnomAD3 exomes AF: 0.0755 AC: 18921 AN: 250604 Hom.: 814 AF XY: 0.0736 AC XY: 9962 AN XY: 135416

Gnomad AFR exome AF: 0.104

Gnomad AMR exome AF: 0.0934

Gnomad ASJ exome AF: 0.0839

Gnomad EAS exome AF: 0.00571

Gnomad SAS exome AF: 0.0532

Gnomad FIN exome AF: 0.0325

Gnomad NFE exome AF: 0.0905

Gnomad OTH exome AF: 0.0798

GnomAD4 exome AF: 0.0859 AC: 125590 AN: 1461310 Hom.: 5869 Cov.: 32 AF XY: 0.0843 AC XY: 61318 AN XY: 727010

Gnomad4 AFR exome AF: 0.102

Gnomad4 AMR exome AF: 0.0941

Gnomad4 ASJ exome AF: 0.0848

Gnomad4 EAS exome AF: 0.00658

Gnomad4 SAS exome AF: 0.0533

Gnomad4 FIN exome AF: 0.0362

Gnomad4 NFE exome AF: 0.0932

Gnomad4 OTH exome AF: 0.0805

GnomAD4 genome AF: 0.0854 AC: 13002 AN: 152248 Hom.: 638 Cov.: 32 AF XY: 0.0812 AC XY: 6046 AN XY: 74462

Gnomad4 AFR AF: 0.105

Gnomad4 AMR AF: 0.0878

Gnomad4 ASJ AF: 0.0879

Gnomad4 EAS AF: 0.00637

Gnomad4 SAS AF: 0.0539

Gnomad4 FIN AF: 0.0282

Gnomad4 NFE AF: 0.0892

Gnomad4 OTH AF: 0.0814

Alfa AF: 0.0915 Hom.: 905

Bravo AF: 0.0925

Asia WGS AF: 0.0420 AC: 148 AN: 3478

EpiCase AF: 0.0939

EpiControl AF: 0.0881

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypogonadotropic hypogonadism 7 with or without anosmia Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Jul 27, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	4.0
DANN	Benign	0.50

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: rs4986942; hg19: chr4-68619601; COSMIC: COSV56933637;