chr4-67740616-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3_StrongPP5_Moderate

The NM_000406.3(GNRHR):ā€‹c.851A>Gā€‹(p.Tyr284Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000373 in 1,610,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā˜…).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000027 ( 0 hom. )

Consequence

GNRHR
NM_000406.3 missense

Scores

11
5
2

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.92
Variant links:
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)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.965
PP5
Variant 4-67740616-T-C is Pathogenic according to our data. Variant chr4-67740616-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16025.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-67740616-T-C is described in UniProt as null.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GNRHRNM_000406.3 linkuse as main transcriptc.851A>G p.Tyr284Cys missense_variant 3/3 ENST00000226413.5 NP_000397.1
GNRHRNM_001012763.2 linkuse as main transcriptc.723A>G p.Leu241= synonymous_variant 3/3 NP_001012781.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GNRHRENST00000226413.5 linkuse as main transcriptc.851A>G p.Tyr284Cys missense_variant 3/31 NM_000406.3 ENSP00000226413 P1P30968-1
UBA6-DTENST00000500538.7 linkuse as main transcriptn.1920+8271T>C intron_variant, non_coding_transcript_variant 1

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152072
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251334
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135836
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1458388
Hom.:
0
Cov.:
29
AF XY:
0.00000276
AC XY:
2
AN XY:
725780
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000271
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
152072
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74284
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.00000961
Hom.:
0
Bravo
AF:
0.0000189
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hypogonadotropic hypogonadism 7 with or without anosmia Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsAug 10, 2021- -
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 01, 1998- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.59
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Pathogenic
0.18
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.78
D
Eigen
Pathogenic
0.72
Eigen_PC
Pathogenic
0.72
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.86
D
M_CAP
Uncertain
0.27
D
MetaRNN
Pathogenic
0.96
D
MetaSVM
Benign
-0.46
T
MutationTaster
Benign
1.0
A;A
PrimateAI
Pathogenic
0.84
D
PROVEAN
Pathogenic
-7.7
D
REVEL
Pathogenic
0.65
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.88
MutPred
0.87
Gain of helix (P = 0.2294);
MVP
0.79
MPC
0.37
ClinPred
1.0
D
GERP RS
5.4
Varity_R
0.85
gMVP
0.81

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs28933074; hg19: chr4-68606334; API