X-38094307-G-A

Position:

• chrX-38094307-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138780.3(SYTL5):​c.844G>A​(p.Glu282Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000092 in 1,086,857 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: SYTL5 NM_138780.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.44

Genes affected

SYTL5 (HGNC:15589): (synaptotagmin like 5) The protein encoded by this gene belongs to the synaptotagmin-like (Slp) protein family, which contains a unique homology domain at the N-terminus, referred to as the Slp homology domain (SHD). The SHD functions as a binding site for Rab27A, which plays a role in protein transport. Expression of this gene is restricted to placenta and liver, suggesting that it might be involved in Rab27A-dependent membrane trafficking in specific tissues. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13831842).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYTL5	NM_138780.3	c.844G>A	p.Glu282Lys	missense_variant	8/17	ENST00000297875.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYTL5	ENST00000297875.7	c.844G>A	p.Glu282Lys	missense_variant	8/17	5	NM_138780.3	P4
SYTL5	ENST00000456733.2	c.844G>A	p.Glu282Lys	missense_variant	7/17	1		A1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.20e-7 AC: 1 AN: 1086857 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 354191

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: 0.00000120

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

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

Dec 21, 2023

The c.844G>A (p.E282K) alteration is located in exon 8 (coding exon 7) of the SYTL5 gene. This alteration results from a G to A substitution at nucleotide position 844, causing the glutamic acid (E) at amino acid position 282 to be replaced by a lysine (K). 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	0.070
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0071	T;.
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	0.77	N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.026
Sift	Benign	0.11	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.24	B;.
Vest4		0.13
MutPred		0.36		Gain of ubiquitination at E282 (P = 0.009);Gain of ubiquitination at E282 (P = 0.009);
MVP		0.10
MPC		0.039
ClinPred		0.68	D
GERP RS		3.1
Varity_R		0.19
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs1024581963; hg19: chrX-37953560;