chr20-45365649-C-T

Variant names:

• chr20-45365649-C-T
• rs1304432844
• NM_033542.4:c.193C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_033542.4(SYS1):​c.193C>T​(p.Leu65Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SYS1 NM_033542.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.87
• 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37334436).

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.193C>T	p.Leu65Phe	missense	Exon 3 of 4	NP_291020.1	Q8N2H4-1
	SYS1	NM_001197129.2		c.193C>T	p.Leu65Phe	missense	Exon 4 of 5	NP_001184058.1	Q8N2H4-1
	SYS1	NM_001099791.3		c.193C>T	p.Leu65Phe	missense	Exon 3 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.193C>T	p.Leu65Phe	missense	Exon 3 of 4	ENSP00000243918.5	Q8N2H4-1
	SYS1	ENST00000453003.1	TSL:1	c.193C>T	p.Leu65Phe	missense	Exon 2 of 3	ENSP00000406879.1	Q5QPU8
	SYS1	ENST00000457307.1	TSL:1	n.*91C>T		non_coding_transcript_exon	Exon 3 of 4	ENSP00000397601.1	F8WB21

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000803 AC: 2 AN: 249060 AF XY: 0.0000148

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: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461884 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Benign	0.046
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.8	L
PhyloP100		4.9
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.36
Sift	Benign	0.074	T
Sift4G	Benign	0.16	T
Polyphen		0.22	B
Vest4		0.81
MutPred		0.65		Loss of catalytic residue at L65 (P = 0.1221)
MVP		0.099
MPC		0.42
ClinPred		0.78	D
GERP RS		4.4
Varity_R		0.19
gMVP		0.63
Mutation Taster		=67/33	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: rs1304432844; hg19: chr20-43994289;