X-38089456-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_138780.3(SYTL5):c.700G>A(p.Gly234Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000176 in 1,205,630 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 57 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., 3 hem., cov: 23)
  • Exomes 𝑓: 0.00018 (0 hom. 54 hem.)
• Consequence: SYTL5 NM_138780.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.63

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05286953).
• BS2: High Hemizygotes in GnomAd at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYTL5	NM_138780.3	c.700G>A	p.Gly234Ser	missense_variant	7/17	ENST00000297875.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYTL5	ENST00000297875.7	c.700G>A	p.Gly234Ser	missense_variant	7/17	5	NM_138780.3	P4
SYTL5	ENST00000456733.2	c.700G>A	p.Gly234Ser	missense_variant	6/17	1		A1

Frequencies

GnomAD3 genomes AF: 0.000180 AC: 20 AN: 111216 Hom.: 0 Cov.: 23 AF XY: 0.0000898 AC XY: 3 AN XY: 33412

Gnomad AFR AF: 0.000131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000191

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: 0.000245

Gnomad OTH AF: 0.000665

GnomAD3 exomes AF: 0.000145 AC: 25 AN: 172173 Hom.: 0 AF XY: 0.0000345 AC XY: 2 AN XY: 58047

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000305

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: 0.000183

Gnomad OTH exome AF: 0.000703

GnomAD4 exome AF: 0.000175 AC: 192 AN: 1094414 Hom.: 0 Cov.: 30 AF XY: 0.000150 AC XY: 54 AN XY: 360342

Gnomad4 AFR exome AF: 0.0000762

Gnomad4 AMR exome AF: 0.000433

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000248

Gnomad4 NFE exome AF: 0.000199

Gnomad4 OTH exome AF: 0.000152

GnomAD4 genome AF: 0.000180 AC: 20 AN: 111216 Hom.: 0 Cov.: 23 AF XY: 0.0000898 AC XY: 3 AN XY: 33412

Gnomad4 AFR AF: 0.000131

Gnomad4 AMR AF: 0.000191

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000245

Gnomad4 OTH AF: 0.000665

Alfa AF: 0.000380 Hom.: 3

Bravo AF: 0.000306

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000446 AC: 3

ExAC AF: 0.0000989 AC: 12

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 03, 2021

The c.700G>A (p.G234S) alteration is located in exon 7 (coding exon 6) of the SYTL5 gene. This alteration results from a G to A substitution at nucleotide position 700, causing the glycine (G) at amino acid position 234 to be replaced by a serine (S). 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	0.073
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.91
Cadd	Benign	15
Dann	Benign	0.75
DEOGEN2	Benign	0.0042	T;.
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.053	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.13	N;N
REVEL	Benign	0.064
Sift	Benign	0.73	T;T
Sift4G	Benign	0.70	T;T
Polyphen		0.0060	B;.
Vest4		0.20
MVP		0.21
MPC		0.037
ClinPred		0.011	T
GERP RS		0.91
Varity_R		0.040
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs372772017; hg19: chrX-37948709;