chr17-46923193-A-G

Variant names:

• chr17-46923193-A-G
• rs879328855
• NM_004287.5:c.1A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 2.63
• Publications: 1 publications found

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

Our verdict: Likely_pathogenic. The variant received 7 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
• 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 VariationId is 1061696.

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

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

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.0000259 AC: 4 AN: 154342 AF XY: 0.0000368

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 FIN exome AF: 0.0000655

Gnomad NFE exome AF: 0.0000169

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000165 AC: 23 AN: 1393564 Hom.: 0 Cov.: 30 AF XY: 0.0000174 AC XY: 12 AN XY: 687692

African (AFR) AF: 0.00 AC: 0 AN: 31496

American (AMR) AF: 0.0000560 AC: 2 AN: 35696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25124

East Asian (EAS) AF: 0.0000560 AC: 2 AN: 35702

South Asian (SAS) AF: 0.0000253 AC: 2 AN: 79114

European-Finnish (FIN) AF: 0.0000407 AC: 2 AN: 49138

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5662

European-Non Finnish (NFE) AF: 0.0000130 AC: 14 AN: 1073852

Other (OTH) AF: 0.0000173 AC: 1 AN: 57780

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74366

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	Progressive myoclonic epilepsy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.034
Eigen_PC	Benign	0.078
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.49	T
PhyloP100		2.6
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.10	B
Vest4		0.78
MutPred		0.84		Loss of disorder (P = 0.2)
MVP		0.80
ClinPred		0.98	D
GERP RS		5.0
PromoterAI		-0.22	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.50
Mutation Taster		=23/177	disease causing

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

Other links and lift over

dbSNP: rs879328855; hg19: chr17-45000559;