8-109575000-G-A

Variant names:

• chr8-109575000-G-A
• rs755298681
• NM_001099754.2:c.1898C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001099754.2(SYBU):​c.1898C>T​(p.Thr633Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000568 in 1,584,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: SYBU NM_001099754.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.671

Genes affected

SYBU (HGNC:26011): (syntabulin) Syntabulin/GOLSYN is part of a kinesin motor-adaptor complex that is critical for the anterograde axonal transport of active zone components and contributes to activity-dependent presynaptic assembly during neuronal development (Cai et al., 2007 [PubMed 17611281]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.060380936).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYBU	NM_001099754.2	c.1898C>T	p.Thr633Met	missense_variant	Exon 7 of 7	ENST00000276646.14	NP_001093224.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYBU	ENST00000276646.14	c.1898C>T	p.Thr633Met	missense_variant	Exon 7 of 7	1	NM_001099754.2	ENSP00000276646.9
SYBU	ENST00000424158.6	c.1913C>T	p.Thr638Met	missense_variant	Exon 9 of 9	1		ENSP00000415654.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000219 AC: 5 AN: 228694 Hom.: 0 AF XY: 0.0000405 AC XY: 5 AN XY: 123406

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000317

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000172

Gnomad SAS exome AF: 0.0000376

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000559 AC: 8 AN: 1432032 Hom.: 0 Cov.: 31 AF XY: 0.00000564 AC XY: 4 AN XY: 708868

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000127

Gnomad4 SAS exome AF: 0.0000122

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000183

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74352

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1898C>T (p.T633M) alteration is located in exon 8 (coding exon 7) of the SYBU gene. This alteration results from a C to T substitution at nucleotide position 1898, causing the threonine (T) at amino acid position 633 to be replaced by a methionine (M). 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	Benign	0.088
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	6.4
DANN	Benign	0.96
DEOGEN2	Benign	0.029	.;T;.;.;.;.;.;T;.;T;T;T;.;T;.;T;T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.82	.;T;T;T;.;.;T;.;T;.;.;T;T;.;.;T;.
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.060	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.2	.;.;.;.;.;.;.;M;.;M;M;M;.;M;.;.;M
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.82	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.061	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.11	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.38	B;.;P;B;B;.;.;B;B;B;B;B;.;B;.;B;B
Vest4		0.093
MutPred		0.32		.;.;.;.;.;.;.;Loss of catalytic residue at T633 (P = 0.0603);.;Loss of catalytic residue at T633 (P = 0.0603);Loss of catalytic residue at T633 (P = 0.0603);Loss of catalytic residue at T633 (P = 0.0603);.;Loss of catalytic residue at T633 (P = 0.0603);.;.;Loss of catalytic residue at T633 (P = 0.0603);
MVP		0.12
MPC		0.53
ClinPred		0.054	T
GERP RS		0.69
Varity_R		0.036
gMVP		0.43

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

LitVar

Other links and lift over

dbSNP: rs755298681; hg19: chr8-110587229; COSMIC: COSV52620410; COSMIC: COSV52620410;