X-38076598-A-G

Position:

• chrX-38076598-A-G

Variant summary

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

The NM_138780.3(SYTL5):​c.586A>G​(p.Arg196Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000915 in 1,093,308 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: 9.1e-7 (0 hom. 0 hem.)
• Consequence: SYTL5 NM_138780.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.56

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=0.20338494).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYTL5	NM_138780.3	c.586A>G	p.Arg196Gly	missense_variant	6/17	ENST00000297875.7	NP_620135.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYTL5	ENST00000297875.7	c.586A>G	p.Arg196Gly	missense_variant	6/17	5	NM_138780.3	ENSP00000297875	P4
SYTL5	ENST00000456733.2	c.586A>G	p.Arg196Gly	missense_variant	5/17	1		ENSP00000395220	A1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.15e-7 AC: 1 AN: 1093308 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 358994

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: 0.0000218

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000756

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

May 20, 2024

The c.586A>G (p.R196G) alteration is located in exon 6 (coding exon 5) of the SYTL5 gene. This alteration results from a A to G substitution at nucleotide position 586, causing the arginine (R) at amino acid position 196 to be replaced by a glycine (G). 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	0.20
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0084	T;.
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	0.91	N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.13
Sift	Benign	0.16	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.19	B;.
Vest4		0.13
MutPred		0.25		Loss of MoRF binding (P = 0.0068);Loss of MoRF binding (P = 0.0068);
MVP		0.43
MPC		0.057
ClinPred		0.88	D
GERP RS		4.0
Varity_R		0.23
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1398475939; hg19: chrX-37935851;