X-38054313-A-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_138780.3(SYTL5):c.220A>T(p.Ile74Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000885 in 1,209,361 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 27 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I74M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., 14 hem., cov: 22)
  • Exomes 𝑓: 0.000054 (0 hom. 13 hem.)
• Consequence: SYTL5 NM_138780.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.25

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2168144).
• BP6: Variant X-38054313-A-T is Benign according to our data. Variant chrX-38054313-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2238894.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High Hemizygotes in GnomAd at 14 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYTL5	NM_138780.3	c.220A>T	p.Ile74Phe	missense_variant	3/17	ENST00000297875.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYTL5	ENST00000297875.7	c.220A>T	p.Ile74Phe	missense_variant	3/17	5	NM_138780.3	P4
SYTL5	ENST00000456733.2	c.220A>T	p.Ile74Phe	missense_variant	2/17	1		A1

Frequencies

GnomAD3 genomes AF: 0.000422 AC: 47 AN: 111287 Hom.: 0 Cov.: 22 AF XY: 0.000418 AC XY: 14 AN XY: 33453

Gnomad AFR AF: 0.00141

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000288

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: 0.000673

GnomAD3 exomes AF: 0.000164 AC: 30 AN: 183234 Hom.: 1 AF XY: 0.000192 AC XY: 13 AN XY: 67728

Gnomad AFR exome AF: 0.00182

Gnomad AMR exome AF: 0.000183

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: 0.000221

GnomAD4 exome AF: 0.0000537 AC: 59 AN: 1098022 Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 13 AN XY: 363394

Gnomad4 AFR exome AF: 0.00167

Gnomad4 AMR exome AF: 0.000171

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: 0.00000119

Gnomad4 OTH exome AF: 0.000174

GnomAD4 genome AF: 0.000431 AC: 48 AN: 111339 Hom.: 0 Cov.: 22 AF XY: 0.000418 AC XY: 14 AN XY: 33515

Gnomad4 AFR AF: 0.00144

Gnomad4 AMR AF: 0.000288

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: 0.000665

Alfa AF: 0.0000126 Hom.: 0

Bravo AF: 0.000654

ESP6500AA AF: 0.00157 AC: 6

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000124 AC: 15

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2021

The c.220A>T (p.I74F) alteration is located in exon 3 (coding exon 2) of the SYTL5 gene. This alteration results from a A to T substitution at nucleotide position 220, causing the isoleucine (I) at amino acid position 74 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

SYTL5-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 09, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	0.060
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.18	T;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.57	P;.
Vest4		0.82
MVP		0.71
MPC		0.21
ClinPred		0.12	T
GERP RS		4.6
Varity_R		0.75
gMVP		0.74

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: rs147486310; hg19: chrX-37913566;