20-45367105-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_033542.4(SYS1):c.461C>T(p.Ser154Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,878 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: 0.0000014 (0 hom.)
• Consequence: SYS1 NM_033542.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.39

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36926967).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYS1	NM_033542.4	c.461C>T	p.Ser154Phe	missense_variant	4/4	ENST00000243918.10
SYS1-DBNDD2	NR_003189.2	n.380+1419C>T		intron_variant, non_coding_transcript_variant
SYS1	NM_001197129.2	c.461C>T	p.Ser154Phe	missense_variant	5/5
SYS1	NM_001099791.3	c.230+1419C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYS1	ENST00000243918.10	c.461C>T	p.Ser154Phe	missense_variant	4/4	1	NM_033542.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461878 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2021

The c.461C>T (p.S154F) alteration is located in exon 5 (coding exon 3) of the SYS1 gene. This alteration results from a C to T substitution at nucleotide position 461, causing the serine (S) at amino acid position 154 to be replaced by a phenylalanine (F). 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	0.45
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.090
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Benign	0.048	T;T;T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.1	M;.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Benign	0.20
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		0.99	D;.;D
Vest4		0.70
MutPred		0.21		Loss of disorder (P = 0.0171);.;Loss of disorder (P = 0.0171);
MVP		0.048
MPC		0.94
ClinPred		0.94	D
GERP RS		5.2
Varity_R		0.33
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-43995745; COSMIC: COSV54782568; COSMIC: COSV54782568;