Variant chr20-45363550-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_033542.4(SYS1):c.19A>T(p.Ser7Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SYS1
NM_033542.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.43

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:

SYS1 (HGNC:):

SYS1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.758

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYS1	NM_033542.4 linkuse as main transcript	c.19A>T	p.Ser7Cys	missense_variant	2/4	ENST00000243918.10	NP_291020.1	Q8N2H4-1
SYS1	NM_001197129.2 linkuse as main transcript	c.19A>T	p.Ser7Cys	missense_variant	3/5		NP_001184058.1	Q8N2H4-1
SYS1	NM_001099791.3 linkuse as main transcript	c.19A>T	p.Ser7Cys	missense_variant	2/4		NP_001093261.1	Q8N2H4-2
SYS1-DBNDD2	NR_003189.2 linkuse as main transcript	n.169A>T		non_coding_transcript_exon_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYS1	ENST00000243918.10 linkuse as main transcript	c.19A>T	p.Ser7Cys	missense_variant	2/4	1	NM_033542.4	ENSP00000243918.5		Q8N2H4-1
SYS1-DBNDD2	ENST00000458187.5 linkuse as main transcript	n.19A>T		non_coding_transcript_exon_variant	1/6	5		ENSP00000457768.1		H3BUS1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1417722

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

702272

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2022

The c.19A>T (p.S7C) alteration is located in exon 3 (coding exon 1) of the SYS1 gene. This alteration results from a A to T substitution at nucleotide position 19, causing the serine (S) at amino acid position 7 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Uncertain

0.093

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

T;T;.;.

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.89

.;D;D;D

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.76

D;D;D;D

MetaSVM

Uncertain

-0.22

MutationAssessor

Uncertain

2.5

M;M;M;.

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-3.1

D;D;D;D

REVEL

Benign

0.27

Sift

Uncertain

0.018

D;D;D;D

Sift4G

Uncertain

0.039

D;D;D;D

Polyphen

1.0

D;D;.;.

Vest4

0.76

MutPred

0.64

Loss of disorder (P = 0.0017);Loss of disorder (P = 0.0017);Loss of disorder (P = 0.0017);Loss of disorder (P = 0.0017);

MVP

0.24

MPC

1.1

ClinPred

0.99

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.51

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over