Genetic Variant SYS1:p.Tyr8His (chr20-45363553-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_033542.4(SYS1):c.22T>C(p.Tyr8His) variant causes a missense change. The variant allele was found at a frequency of 0.000000703 in 1,423,064 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

SYS1
NM_033542.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.53

Publications

0 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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.22T>C	p.Tyr8His	missense	Exon 2 of 4	NP_291020.1	Q8N2H4-1
SYS1	NM_001197129.2		c.22T>C	p.Tyr8His	missense	Exon 3 of 5	NP_001184058.1	Q8N2H4-1
SYS1	NM_001099791.3		c.22T>C	p.Tyr8His	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.22T>C	p.Tyr8His	missense	Exon 2 of 4	ENSP00000243918.5	Q8N2H4-1
SYS1	ENST00000453003.1	TSL:1	c.22T>C	p.Tyr8His	missense	Exon 1 of 3	ENSP00000406879.1	Q5QPU8
SYS1	ENST00000457307.1	TSL:1	n.22T>C		non_coding_transcript_exon	Exon 2 of 4	ENSP00000397601.1	F8WB21

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.03e-7

AC:

AN:

1423064

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

705244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32704

American (AMR)

AF:

0.00

AC:

AN:

39746

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25454

East Asian (EAS)

AF:

0.00

AC:

AN:

37590

South Asian (SAS)

AF:

0.00

AC:

AN:

82044

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46882

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5654

European-Non Finnish (NFE)

AF:

9.14e-7

AC:

AN:

1094080

Other (OTH)

AF:

0.00

AC:

AN:

58910

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.046

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.023

MetaRNN

Uncertain

0.47

MetaSVM

Benign

-0.70

MutationAssessor

Benign

1.7

PhyloP100

5.5

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.2

REVEL

Benign

0.18

Sift

Benign

0.037

Sift4G

Benign

0.38

Polyphen

0.93

Vest4

0.69

MutPred

0.58

Gain of disorder (P = 0.0274)

MVP

0.24

MPC

0.46

ClinPred

0.96

GERP RS

4.6

PromoterAI

-0.21

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.35

gMVP

0.51

Mutation Taster

=255/45

polymorphism

(source)

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

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over