rs2307890

chr1-210094548-TGAA-Tchr1-210094548-TGAA-TGAAGAA

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PM4_Supporting BP6 BA1

The NM_001146262.4(SYT14):c.675_677del(p.Glu225del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,613,578 control chromosomes in the GnomAD database, including 14,767 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.10 (1090 hom., cov: 31)
  • Exomes 𝑓: 0.13 (13677 hom.)
• Consequence: SYT14 NM_001146262.4 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 9.35

Genes affected

SYT14 (HGNC:23143): (synaptotagmin 14) This gene is a member of the synaptotagmin gene family and encodes a protein similar to other family members that mediate membrane trafficking in synaptic transmission. The encoded protein is a calcium-independent synaptotagmin. Mutations in this gene are a cause of autosomal recessive spinocerebellar ataxia-11 (SCAR11), and a t(1;3) translocation of this gene has been associated with neurodevelopmental abnormalities. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 4. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001146262.4. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 1-210094548-TGAA-T is Benign according to our data. Variant chr1-210094548-TGAA-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212360.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1, Likely_benign=1}. Variant chr1-210094548-TGAA-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.135 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYT14	NM_001146262.4	c.675_677del	p.Glu225del	inframe_deletion	5/9	ENST00000367019.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYT14	ENST00000367019.6	c.675_677del	p.Glu225del	inframe_deletion	5/9	1	NM_001146262.4

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15575 AN: 152042 Hom.: 1091 Cov.: 31

Gnomad AFR AF: 0.0248

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.0764

Gnomad ASJ AF: 0.0714

Gnomad EAS AF: 0.0866

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.225

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.0909

GnomAD3 exomes AF: 0.116 AC: 29060 AN: 249712 Hom.: 2042 AF XY: 0.120 AC XY: 16241 AN XY: 135062

Gnomad AFR exome AF: 0.0218

Gnomad AMR exome AF: 0.0564

Gnomad ASJ exome AF: 0.0691

Gnomad EAS exome AF: 0.0755

Gnomad SAS exome AF: 0.120

Gnomad FIN exome AF: 0.217

Gnomad NFE exome AF: 0.139

Gnomad OTH exome AF: 0.120

GnomAD4 exome AF: 0.132 AC: 193418 AN: 1461418 Hom.: 13677 AF XY: 0.133 AC XY: 96390 AN XY: 726994

Gnomad4 AFR exome AF: 0.0202

Gnomad4 AMR exome AF: 0.0601

Gnomad4 ASJ exome AF: 0.0707

Gnomad4 EAS exome AF: 0.102

Gnomad4 SAS exome AF: 0.121

Gnomad4 FIN exome AF: 0.214

Gnomad4 NFE exome AF: 0.139

Gnomad4 OTH exome AF: 0.118

GnomAD4 genome AF: 0.102 AC: 15572 AN: 152160 Hom.: 1090 Cov.: 31 AF XY: 0.107 AC XY: 7943 AN XY: 74370

Gnomad4 AFR AF: 0.0247

Gnomad4 AMR AF: 0.0763

Gnomad4 ASJ AF: 0.0714

Gnomad4 EAS AF: 0.0866

Gnomad4 SAS AF: 0.129

Gnomad4 FIN AF: 0.225

Gnomad4 NFE AF: 0.137

Gnomad4 OTH AF: 0.0900

Alfa AF: 0.113 Hom.: 224

Bravo AF: 0.0875

Asia WGS AF: 0.0840 AC: 294 AN: 3478

EpiCase AF: 0.132

EpiControl AF: 0.135

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive spinocerebellar ataxia 11 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 15, 2014

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs2307890; hg19: chr1-210267893;