1-209965877-C-CTT

Variant names:

• chr1-209965877-C-CTT
• rs752741374
• NM_001146262.4:c.61+13133_61+13134dupTT

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PVS1_Moderate BP6

The NM_001146261.4(SYT14):​c.76-4_76-3dupTT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00059 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SYT14 NM_001146261.4 splice_acceptor, intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.186
• Publications: 0 publications found

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]

SYT14 Gene-Disease associations (from GenCC):

• autosomal recessive spinocerebellar ataxia 11

  Inheritance: Unknown, AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.06505376 fraction of the gene. Cryptic splice site detected, with MaxEntScore 12, offset of 0 (no position change), new splice context is: ttctttttttttttttttAGata. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BP6: Variant 1-209965877-C-CTT is Benign according to our data. Variant chr1-209965877-C-CTT is described in ClinVar as Likely_benign. ClinVar VariationId is 3047989.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001146261.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYT14	NM_001146262.4	MANE Select	c.61+13133_61+13134dupTT		intron	N/A	NP_001139734.1	Q8NB59-6
	SYT14	NM_001397544.1		c.-989+13133_-989+13134dupTT		intron	N/A	NP_001384473.1	A0A8V8TN09
	SYT14	NM_001397545.1		c.-989+12630_-989+12631dupTT		intron	N/A	NP_001384474.1	A0A8V8TN09

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYT14	ENST00000367019.6	TSL:1 MANE Select	c.61+13121_61+13122insTT		intron	N/A	ENSP00000355986.1	Q8NB59-6
	SYT14	ENST00000472886.5	TSL:1	c.61+13121_61+13122insTT		intron	N/A	ENSP00000418901.1	Q8NB59-1
	SYT14	ENST00000367015.5	TSL:1	c.-54+12618_-54+12619insTT		intron	N/A	ENSP00000355982.1	Q8NB59-3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 140276 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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

GnomAD2 exomes AF: 0.00113 AC: 74 AN: 65388 AF XY: 0.00128

Gnomad AFR exome AF: 0.00152

Gnomad AMR exome AF: 0.00135

Gnomad ASJ exome AF: 0.000761

Gnomad EAS exome AF: 0.000978

Gnomad FIN exome AF: 0.000700

Gnomad NFE exome AF: 0.00102

Gnomad OTH exome AF: 0.000952

GnomAD4 exome AF: 0.000587 AC: 155 AN: 264232 Hom.: 0 Cov.: 0 AF XY: 0.000560 AC XY: 85 AN XY: 151748

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000726 AC: 5 AN: 6890

American (AMR) AF: 0.000658 AC: 15 AN: 22802

Ashkenazi Jewish (ASJ) AF: 0.000211 AC: 2 AN: 9474

East Asian (EAS) AF: 0.000856 AC: 7 AN: 8178

South Asian (SAS) AF: 0.000486 AC: 25 AN: 51404

European-Finnish (FIN) AF: 0.000719 AC: 8 AN: 11124

Middle Eastern (MID) AF: 0.000483 AC: 1 AN: 2072

European-Non Finnish (NFE) AF: 0.000614 AC: 86 AN: 140084

Other (OTH) AF: 0.000492 AC: 6 AN: 12204

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 140276 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 68040

African (AFR) AF: 0.00 AC: 0 AN: 38352

American (AMR) AF: 0.00 AC: 0 AN: 13978

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3276

East Asian (EAS) AF: 0.00 AC: 0 AN: 4858

South Asian (SAS) AF: 0.00 AC: 0 AN: 4390

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8694

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 63660

Other (OTH) AF: 0.00 AC: 0 AN: 1894

Alfa AF: 0.000915 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	SYT14-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.19

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs752741374; hg19: chr1-210139222;