rs4986942

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr4-67753883-G-A
• chr4-67753883-G-C
• chr4-67753883-G-T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 14 publications found

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

Our verdict: Benign. The variant received -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 VariationId is 349456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000406.3. 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
	GNRHR	NM_000406.3	MANE Select	c.453C>T	p.Ser151Ser	synonymous	Exon 1 of 3	NP_000397.1	P30968-1
	GNRHR	NM_001012763.2		c.453C>T	p.Ser151Ser	synonymous	Exon 1 of 3	NP_001012781.1	P30968-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNRHR	ENST00000226413.5	TSL:1 MANE Select	c.453C>T	p.Ser151Ser	synonymous	Exon 1 of 3	ENSP00000226413.5	P30968-1
	GNRHR	ENST00000420975.2	TSL:1	c.453C>T	p.Ser151Ser	synonymous	Exon 1 of 3	ENSP00000397561.2	P30968-2
	UBA6-DT	ENST00000500538.7	TSL:1	n.1921-1306G>A		intron	N/A

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

GnomAD2 exomes AF: 0.0755 AC: 18921 AN: 250604 AF XY: 0.0736

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 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

African (AFR) AF: 0.102 AC: 3421 AN: 33476

American (AMR) AF: 0.0941 AC: 4203 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.0848 AC: 2216 AN: 26128

East Asian (EAS) AF: 0.00658 AC: 261 AN: 39690

South Asian (SAS) AF: 0.0533 AC: 4600 AN: 86250

European-Finnish (FIN) AF: 0.0362 AC: 1932 AN: 53384

Middle Eastern (MID) AF: 0.0883 AC: 509 AN: 5764

European-Non Finnish (NFE) AF: 0.0932 AC: 103589 AN: 1111594

Other (OTH) AF: 0.0805 AC: 4859 AN: 60366

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

African (AFR) AF: 0.105 AC: 4346 AN: 41542

American (AMR) AF: 0.0878 AC: 1342 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0879 AC: 305 AN: 3470

East Asian (EAS) AF: 0.00637 AC: 33 AN: 5182

South Asian (SAS) AF: 0.0539 AC: 260 AN: 4828

European-Finnish (FIN) AF: 0.0282 AC: 299 AN: 10616

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0892 AC: 6066 AN: 68000

Other (OTH) AF: 0.0814 AC: 172 AN: 2112

Alfa AF: 0.0915 Hom.: 1245

Bravo AF: 0.0925

Asia WGS AF: 0.0420 AC: 148 AN: 3478

EpiCase AF: 0.0939

EpiControl AF: 0.0881

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Hypogonadotropic hypogonadism 7 with or without anosmia (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	4.0
DANN	Benign	0.50
PhyloP100		1.1
PromoterAI		-0.065	Neutral
Mutation Taster		=100/0	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: rs4986942; hg19: chr4-68619601; COSMIC: COSV56933637;