chr17-46923195-G-A

Variant names:

• chr17-46923195-G-A
• NM_004287.5:c.3G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The NM_004287.5(GOSR2):​c.3G>A​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000143 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: 0.0000014 (0 hom.)
• Consequence: GOSR2 NM_004287.5 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.51

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]

ENSG00000262633 (HGNC:):

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]

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

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GOSR2	NM_004287.5	c.3G>A	p.Met1?	start_lost	Exon 1 of 6	ENST00000640051.2	NP_004278.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GOSR2	ENST00000640051.2	c.3G>A	p.Met1?	start_lost	Exon 1 of 6	1	NM_004287.5	ENSP00000492751.1
ENSG00000262633	ENST00000571841.1	n.3G>A		non_coding_transcript_exon_variant	Exon 1 of 10	5		ENSP00000461460.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1394166 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 687936

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000280

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.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Progressive myoclonic epilepsy Uncertain:1

Jan 20, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals with GOSR2-related conditions. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant is not present in population databases (ExAC 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	D
BayesDel_noAF	Pathogenic	0.30
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	.;.;.;.;.;.;T;.;.;.;.;.;.;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.27	T
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	D
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-45000561; COSMIC: COSV56664831; COSMIC: COSV56664831;