Variant 17-46923195-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001363851.2(GOSR2):c.-463G>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000000717 in 1,394,166 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

GOSR2
NM_001363851.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.51

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:

ENSG00000262633 (HGNC:):

ENSG00000262633 links:

LRRC37A2 (HGNC:32404): (leucine rich repeat containing 37 member A2) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

LRRC37A2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.976

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GOSR2	NM_004287.5 link	c.3G>T	p.Met1?	start_lost	1/6	ENST00000640051.2	NP_004278.2	O14653-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GOSR2	ENST00000640051.2 link	c.3G>T	p.Met1?	start_lost	1/6	1	NM_004287.5	ENSP00000492751.1		O14653-1
ENSG00000262633	ENST00000571841.1 link	n.3G>T		non_coding_transcript_exon_variant	1/10	5		ENSP00000461460.1		E7EQ34

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.17e-7

AC:

AN:

1394166

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

687936

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.31e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Progressive myoclonic epilepsy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 22, 2022

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. Disruption of the initiator codon has been observed in individual(s) with clinical features of GOSR2-related conditions (PMID: 29855340). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the GOSR2 mRNA. The next in-frame methionine is located at codon 19. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.30

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

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

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.90

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

M_CAP

Pathogenic

0.65

MetaRNN

Pathogenic

0.98

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

MetaSVM

Uncertain

-0.27

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

0.89, 0.32

.;.;.;P;.;.;B;.;.;.;.;.;.;.

Vest4

0.78, 0.78, 0.79, 0.77

MutPred

0.83

Gain of catalytic residue at M1 (P = 0.0328);Gain of catalytic residue at M1 (P = 0.0328);Gain of catalytic residue at M1 (P = 0.0328);Gain of catalytic residue at M1 (P = 0.0328);Gain of catalytic residue at M1 (P = 0.0328);Gain of catalytic residue at M1 (P = 0.0328);Gain of catalytic residue at M1 (P = 0.0328);Gain of catalytic residue at M1 (P = 0.0328);Gain of catalytic residue at M1 (P = 0.0328);Gain of catalytic residue at M1 (P = 0.0328);Gain of catalytic residue at M1 (P = 0.0328);Gain of catalytic residue at M1 (P = 0.0328);Gain of catalytic residue at M1 (P = 0.0328);Gain of catalytic residue at M1 (P = 0.0328);

MVP

0.82

ClinPred

1.0

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

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