chr17-46923193-A-G

Position:

chr17-46923193-A-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1PS1_ModeratePM2PP5

The NM_004287.5(GOSR2):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,545,790 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

GOSR2
NM_004287.5 start_lost

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2

Conservation

PhyloP100: 2.63

Variant links:

Genes affected

GOSR2 (HGNC:4431): (golgi SNAP receptor complex member 2) This gene encodes a trafficking membrane protein which transports proteins among the medial- and trans-Golgi compartments. Due to its chromosomal location and trafficking function, this gene may be involved in familial essential hypertension. [provided by RefSeq, Mar 2016]

GOSR2 links:

LRRC37A2 (HGNC:):

LRRC37A2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PS1

Another start lost variant in NM_004287.5 (GOSR2) was described as [Pathogenic] in ClinVar as 1324496

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-46923193-A-G is Pathogenic according to our data. Variant chr17-46923193-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1061696.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GOSR2	NM_004287.5 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/6	ENST00000640051.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GOSR2	ENST00000640051.2 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/6	1	NM_004287.5	P3	O14653-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

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:

0.00

GnomAD3 exomes

AF:

0.0000259

AC:

AN:

154342

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

81628

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000809

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000655

Gnomad NFE exome

AF:

0.0000169

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000165

AC:

AN:

1393564

Hom.:

Cov.:

AF XY:

0.0000174

AC XY:

AN XY:

687692

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000560

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000560

Gnomad4 SAS exome

AF:

0.0000253

Gnomad4 FIN exome

AF:

0.0000407

Gnomad4 NFE exome

AF:

0.0000130

Gnomad4 OTH exome

AF:

0.0000173

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74366

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:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 27, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2020	Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2019

The p.M1? variant (also known as c.1A>G) is located in coding exon 1 of the GOSR2 gene and results from a A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. Variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame; however, there is an alternate in-frame methionine 18 amino acids from the initiation site and the significance of the N-terminus for this protein is not well established. Since supporting evidence is limited at this time, the clinical significance remains unclear. -

Progressive myoclonic epilepsy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 25, 2022

This sequence change affects the initiator methionine of the GOSR2 mRNA. The next in-frame methionine is located at codon 19. This variant is present in population databases (no rsID available, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with GOSR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1061696). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.27

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

.;.;.;.;.;.;T;.;.;.;.;.;.;.

Eigen

Benign

-0.034

Eigen_PC

Benign

0.078

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.90

D;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.49

MutationTaster

Benign

1.0

D;D;D;D;D;D

PROVEAN

Uncertain

-3.4

.;.;.;D;D;.;.;.;.;.;.;.;.;.

REVEL

Uncertain

0.55

Sift

Pathogenic

0.0

.;.;.;D;D;.;.;.;.;.;.;.;.;.

Sift4G

Pathogenic

0.0

.;.;.;D;D;D;.;.;.;.;D;.;.;.

Polyphen

0.10, 0.019

.;.;.;B;.;.;B;.;.;.;.;.;.;.

Vest4

0.78, 0.79, 0.79, 0.78

MutPred

0.84

Loss of disorder (P = 0.2);Loss of disorder (P = 0.2);Loss of disorder (P = 0.2);Loss of disorder (P = 0.2);Loss of disorder (P = 0.2);Loss of disorder (P = 0.2);Loss of disorder (P = 0.2);Loss of disorder (P = 0.2);Loss of disorder (P = 0.2);Loss of disorder (P = 0.2);Loss of disorder (P = 0.2);Loss of disorder (P = 0.2);Loss of disorder (P = 0.2);Loss of disorder (P = 0.2);

MVP

0.80

ClinPred

0.98

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

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

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