rs4827331

chrX-38089579-A-CchrX-38089579-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.823A>C(p.Ile275Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000249 in 1,206,467 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I275V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: SYTL5 NM_138780.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.98

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=0.07240504).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYTL5	NM_138780.3	c.823A>C	p.Ile275Leu	missense_variant	7/17	ENST00000297875.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYTL5	ENST00000297875.7	c.823A>C	p.Ile275Leu	missense_variant	7/17	5	NM_138780.3	P4
SYTL5	ENST00000456733.2	c.823A>C	p.Ile275Leu	missense_variant	6/17	1		A1

Frequencies

GnomAD3 genomes AF: 0.00000899 AC: 1 AN: 111276 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33484

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000950

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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: 0.0000113 AC: 2 AN: 176956 Hom.: 0 AF XY: 0.0000161 AC XY: 1 AN XY: 62292

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000745

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1095191 Hom.: 0 Cov.: 30 AF XY: 0.00000277 AC XY: 1 AN XY: 360919

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000573

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: 0.00

GnomAD4 genome AF: 0.00000899 AC: 1 AN: 111276 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33484

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000950

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.94
Cadd	Benign	7.7
Dann	Benign	0.64
DEOGEN2	Benign	0.0050	T;.
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.58	T;T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.072	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.030	N;N
REVEL	Benign	0.040
Sift	Benign	0.44	T;T
Sift4G	Benign	0.77	T;T
Polyphen		0.0	B;.
Vest4		0.094
MutPred		0.13		Gain of phosphorylation at T272 (P = 0.0959);Gain of phosphorylation at T272 (P = 0.0959);
MVP		0.21
MPC		0.036
ClinPred		0.028	T
GERP RS		3.9
Varity_R		0.093
gMVP		0.18

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

LitVar

Other links and lift over

dbSNP: rs4827331; hg19: chrX-37948832;