Genetic Variant SYS1:p.Leu34Met (chr20-45363631-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_033542.4(SYS1):c.100C>A(p.Leu34Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L34L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SYS1
NM_033542.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.16

Publications

2 publications found

Variant links:

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 links:

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]

SYS1-DBNDD2 links:

ENSG00000305954 (HGNC:):

ENSG00000305954 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2286781).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SYS1	NM_033542.4	MANE Select	c.100C>A	p.Leu34Met	missense	Exon 2 of 4	NP_291020.1	Q8N2H4-1
SYS1	NM_001197129.2		c.100C>A	p.Leu34Met	missense	Exon 3 of 5	NP_001184058.1	Q8N2H4-1
SYS1	NM_001099791.3		c.100C>A	p.Leu34Met	missense	Exon 2 of 4	NP_001093261.1	Q8N2H4-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SYS1	ENST00000243918.10	TSL:1 MANE Select	c.100C>A	p.Leu34Met	missense	Exon 2 of 4	ENSP00000243918.5	Q8N2H4-1
SYS1	ENST00000453003.1	TSL:1	c.100C>A	p.Leu34Met	missense	Exon 1 of 3	ENSP00000406879.1	Q5QPU8
SYS1	ENST00000457307.1	TSL:1	n.100C>A		non_coding_transcript_exon	Exon 2 of 4	ENSP00000397601.1	F8WB21

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

195454

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1431934

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

710118

African (AFR)

AF:

0.00

AC:

AN:

32824

American (AMR)

AF:

0.00

AC:

AN:

40140

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25612

East Asian (EAS)

AF:

0.00

AC:

AN:

37862

South Asian (SAS)

AF:

0.00

AC:

AN:

82460

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49486

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1098502

Other (OTH)

AF:

0.00

AC:

AN:

59316

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.037

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.031

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.010

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.78

M_CAP

Benign

0.010

MetaRNN

Benign

0.23

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.4

PhyloP100

1.2

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.48

REVEL

Benign

0.15

Sift

Benign

0.25

Sift4G

Benign

0.38

Polyphen

0.27

Vest4

0.34

MutPred

0.50

Gain of catalytic residue at A35 (P = 0.5569)

MVP

0.12

MPC

0.46

ClinPred

0.82

GERP RS

3.3

PromoterAI

0.063

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.17

gMVP

0.64

Mutation Taster

=84/16

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over