1-155868657-C-T

Variant names:

• chr1-155868657-C-T
• NM_152280.5:c.727C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_152280.5(SYT11):​c.727C>T​(p.His243Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SYT11 NM_152280.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.97
• Publications: 0 publications found

Genes affected

SYT11 (HGNC:19239): (synaptotagmin 11) This gene is a member of the synaptotagmin gene family and encodes a protein similar to other family members that are known calcium sensors and mediate calcium-dependent regulation of membrane trafficking in synaptic transmission. The encoded protein is also a substrate for ubiquitin-E3-ligase parkin. The gene has previously been referred to as synaptotagmin XII but has been renamed synaptotagmin XI to be consistent with mouse and rat official nomenclature. [provided by RefSeq, Apr 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.835

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYT11	NM_152280.5	c.727C>T	p.His243Tyr	missense_variant	Exon 2 of 4	ENST00000368324.5	NP_689493.3
SYT11	XM_017000759.3	c.727C>T	p.His243Tyr	missense_variant	Exon 2 of 4		XP_016856248.1
SYT11	XM_005245014.4	c.727C>T	p.His243Tyr	missense_variant	Exon 2 of 4		XP_005245071.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYT11	ENST00000368324.5	c.727C>T	p.His243Tyr	missense_variant	Exon 2 of 4	1	NM_152280.5	ENSP00000357307.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 17, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.727C>T (p.H243Y) alteration is located in exon 2 (coding exon 2) of the SYT11 gene. This alteration results from a C to T substitution at nucleotide position 727, causing the histidine (H) at amino acid position 243 to be replaced by a tyrosine (Y). 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	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	-0.099	T
MutationAssessor	Benign	2.0	M
PhyloP100		6.0
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.099	T
Polyphen		1.0	D
Vest4		0.82
MutPred		0.54		Loss of catalytic residue at L245 (P = 0.115);
MVP		0.36
MPC		1.4
ClinPred		0.98	D
GERP RS		6.0
Varity_R		0.85
gMVP		0.61
Mutation Taster		=19/81	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

hg19: chr1-155838448;