chr20-45363550-A-G

Variant names:

• chr20-45363550-A-G
• rs1568915943
• NM_033542.4:c.19A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_033542.4(SYS1):​c.19A>G​(p.Ser7Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000705 in 1,417,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S7C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: SYS1 NM_033542.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.43
• Publications: 0 publications found

Genes affected

SYS1 (HGNC:16162): (SYS1 golgi trafficking protein) SYS1 forms a complex with ADP-ribosylation factor-related protein ARFRP1 (MIM 604699) and targets ARFRP1 to the Golgi apparatus (Behnia et al., 2004 [PubMed 15077113]).[supplied by OMIM, Aug 2009]

SYS1-DBNDD2 (HGNC:33535): (SYS1-DBNDD2 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription from the neighboring SYS1 Golgi-localized integral membrane protein homolog and dysbindin domain containing 2 (DBNDD2) genes. The read-through transcript includes the majority of exons from each individual gene, but it would be subject to nonsense-mediated mRNA decay (NMD) and is therefore predicted to be non-coding. [provided by RefSeq, Oct 2010]

ENSG00000305954 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.767

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033542.4. 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
	SYS1	NM_033542.4	MANE Select	c.19A>G	p.Ser7Gly	missense	Exon 2 of 4	NP_291020.1	Q8N2H4-1
	SYS1	NM_001197129.2		c.19A>G	p.Ser7Gly	missense	Exon 3 of 5	NP_001184058.1	Q8N2H4-1
	SYS1	NM_001099791.3		c.19A>G	p.Ser7Gly	missense	Exon 2 of 4	NP_001093261.1	Q8N2H4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYS1	ENST00000243918.10	TSL:1 MANE Select	c.19A>G	p.Ser7Gly	missense	Exon 2 of 4	ENSP00000243918.5	Q8N2H4-1
	SYS1	ENST00000453003.1	TSL:1	c.19A>G	p.Ser7Gly	missense	Exon 1 of 3	ENSP00000406879.1	Q5QPU8
	SYS1	ENST00000457307.1	TSL:1	n.19A>G		non_coding_transcript_exon	Exon 2 of 4	ENSP00000397601.1	F8WB21

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000547 AC: 1 AN: 182724 AF XY: 0.0000101

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000130

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.05e-7 AC: 1 AN: 1417722 Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1 AN XY: 702272

African (AFR) AF: 0.00 AC: 0 AN: 32580

American (AMR) AF: 0.00 AC: 0 AN: 39136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25334

East Asian (EAS) AF: 0.00 AC: 0 AN: 37338

South Asian (SAS) AF: 0.00 AC: 0 AN: 81602

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46024

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5446

European-Non Finnish (NFE) AF: 9.16e-7 AC: 1 AN: 1091546

Other (OTH) AF: 0.00 AC: 0 AN: 58716

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.065	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.077	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.4
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.49
Sift	Benign	0.073	T
Sift4G	Benign	0.12	T
Polyphen		0.99	D
Vest4		0.37
MutPred		0.64		Loss of stability (P = 0.0305)
MVP		0.25
MPC		0.91
ClinPred		0.98	D
GERP RS		4.6
PromoterAI		-0.027	Neutral
Varity_R		0.49
gMVP		0.55
Mutation Taster		=247/53	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1568915943; hg19: chr20-43992190;