chr20-3044684-G-A

Position:

chr20-3044684-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The ENST00000245983.6(GNRH2):c.160G>A(p.Ala54Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00395 in 1,608,710 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0087 ( 12 hom., cov: 33)

Exomes 𝑓: 0.0034 ( 58 hom. )

Consequence

GNRH2
ENST00000245983.6 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.415

Variant links:

Genes affected

GNRH2 (HGNC:4420): (gonadotropin releasing hormone 2) This gene is a member of the gonadotropin-releasing hormone (GnRH) gene family. Proteins encoded by members of this gene family are proteolytically cleaved to form neuropeptides which, in part, regulate reproductive functions by stimulating the production and release of the gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The human GNRH2 gene is predicted to encode a preproprotein from which a mature neuropeptide of 10 amino acids is cleaved. However, while the human genome retains the sequence for a functional GNRH2 decapeptide, translation of the human GNRH2 gene has not yet been demonstrated and the GNRH2 gene of chimpanzees, gorilla, and Sumatran orangutan have a premature stop at codon eight of the decapeptide sequence which suggests GNRH2 was a pseudogene in the hominid lineage. The GNRH2 gene is also believed to be a pseudogene in many other mammalian species such as mouse and cow. The receptor for this gene (GNRHR2) is predicted to be a pseudogene in human as well as many other mammalian species. The closely related GNRH1 and GNRHR1 genes are functional in human and other mammals and are generally functional in vertebrates. [provided by RefSeq, Mar 2019]

GNRH2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025749207).

BP6

Variant 20-3044684-G-A is Benign according to our data. Variant chr20-3044684-G-A is described in ClinVar as [Benign]. Clinvar id is 786673.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00875 (1332/152298) while in subpopulation AFR AF= 0.0242 (1005/41570). AF 95% confidence interval is 0.0229. There are 12 homozygotes in gnomad4. There are 681 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GNRH2	NM_178331.2 linkuse as main transcript	c.155-16G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000359100.6
GNRH2	NM_001310220.2 linkuse as main transcript	c.160G>A	p.Ala54Thr	missense_variant	3/4
GNRH2	NM_001501.2 linkuse as main transcript	c.160G>A	p.Ala54Thr	missense_variant	3/4
GNRH2	NM_178332.2 linkuse as main transcript	c.155-19G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNRH2	ENST00000245983.6 linkuse as main transcript	c.160G>A	p.Ala54Thr	missense_variant	3/4	1		P2	O43555-1
GNRH2	ENST00000359100.6 linkuse as main transcript	c.155-16G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_178331.2	A2	O43555-3
GNRH2	ENST00000380346.2 linkuse as main transcript	c.155-19G>A		intron_variant		2		A2	O43555-2
GNRH2	ENST00000380347.6 linkuse as main transcript	c.155-16G>A		splice_polypyrimidine_tract_variant, intron_variant		5		A2	O43555-3

Frequencies

GnomAD3 genomes

AF:

0.00875

AC:

1331

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00622

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00482

Gnomad SAS

AF:

0.0238

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.000941

Gnomad OTH

AF:

0.0100

GnomAD3 exomes

AF:

0.00615

AC:

1506

AN:

244846

Hom.:

AF XY:

0.00666

AC XY:

885

AN XY:

132800

show subpopulations

Gnomad AFR exome

AF:

0.0251

Gnomad AMR exome

AF:

0.00585

Gnomad ASJ exome

AF:

0.000305

Gnomad EAS exome

AF:

0.00209

Gnomad SAS exome

AF:

0.0230

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00124

Gnomad OTH exome

AF:

0.00704

GnomAD4 exome

AF:

0.00344

AC:

5016

AN:

1456412

Hom.:

Cov.:

AF XY:

0.00400

AC XY:

2894

AN XY:

723608

show subpopulations

Gnomad4 AFR exome

AF:

0.0251

Gnomad4 AMR exome

AF:

0.00600

Gnomad4 ASJ exome

AF:

0.000307

Gnomad4 EAS exome

AF:

0.0117

Gnomad4 SAS exome

AF:

0.0223

Gnomad4 FIN exome

AF:

0.0000568

Gnomad4 NFE exome

AF:

0.000981

Gnomad4 OTH exome

AF:

0.00588

GnomAD4 genome

AF:

0.00875

AC:

1332

AN:

152298

Hom.:

Cov.:

AF XY:

0.00915

AC XY:

681

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0242

Gnomad4 AMR

AF:

0.00621

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00484

Gnomad4 SAS

AF:

0.0238

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000941

Gnomad4 OTH

AF:

0.00993

Alfa

AF:

0.00255

Hom.:

Bravo

AF:

0.00976

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.0236

AC:

104

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.00688

AC:

835

Asia WGS

AF:

0.0210

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.60

CADD

Benign

3.3

DANN

Uncertain

0.99

DEOGEN2

Benign

0.045

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.073

LIST_S2

Benign

0.41

MetaRNN

Benign

0.0026

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.41

PROVEAN

Benign

0.23

REVEL

Benign

0.0060

Sift

Benign

0.21

Sift4G

Benign

0.35

Polyphen

0.025

Vest4

0.12

MVP

0.095

MPC

0.043

ClinPred

0.0069

GERP RS

-1.6

Varity_R

0.034

gMVP

0.032

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over