Genetic Variant NM_004287.5:c.3G>C (chr17-46923195-G-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_StrongPM2

The NM_004287.5(GOSR2):c.3G>C(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000717 in 1,394,164 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_004287.5 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.51

Publications

0 publications found

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:

GOSR2-DT (HGNC:55346): (GOSR2 divergent transcript)

GOSR2-DT links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 5 pathogenic variants. Next in-frame start position is after 19 codons. Genomic position: 46929545. Lost 0.086 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004287.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GOSR2	NM_004287.5	MANE Select	c.3G>C	p.Met1?	start_lost	Exon 1 of 6	NP_004278.2
GOSR2	NM_001321133.2		c.3G>C	p.Met1?	start_lost	Exon 1 of 7	NP_001308062.1	I3NI02
GOSR2	NM_054022.4		c.3G>C	p.Met1?	start_lost	Exon 1 of 7	NP_473363.1	O14653-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GOSR2	ENST00000640051.2	TSL:1 MANE Select	c.3G>C	p.Met1?	start_lost	Exon 1 of 6	ENSP00000492751.1	O14653-1
GOSR2	ENST00000225567.9	TSL:1	c.3G>C	p.Met1?	start_lost	Exon 1 of 7	ENSP00000225567.4	O14653-2
GOSR2	ENST00000640621.1	TSL:1	c.3G>C	p.Met1?	start_lost	Exon 1 of 5	ENSP00000492830.1	O14653-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.17e-7

AC:

AN:

1394164

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

687936

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31514

American (AMR)

AF:

0.00

AC:

AN:

35694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25122

East Asian (EAS)

AF:

0.00

AC:

AN:

35696

South Asian (SAS)

AF:

0.00

AC:

AN:

79124

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49140

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5666

European-Non Finnish (NFE)

AF:

9.31e-7

AC:

AN:

1074410

Other (OTH)

AF:

0.00

AC:

AN:

57798

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Progressive myoclonic epilepsy type 6;C5774274:Muscular dystrophy, congenital, with or without seizures (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.30

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.65

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

-0.27

PhyloP100

4.5

PROVEAN

Uncertain

-3.4

REVEL

Uncertain

0.54

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.89

Vest4

0.78

MutPred

0.83

Gain of catalytic residue at M1 (P = 0.0328)

MVP

0.82

ClinPred

1.0

GERP RS

5.0

PromoterAI

-0.18

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.44

Mutation Taster

=11/189

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over