chrX-100686087-C-G

Variant names:

• chrX-100686087-C-G
• NM_001370165.1:c.1352G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001370165.1(SYTL4):​c.1352G>C​(p.Arg451Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,582 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R451C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: SYTL4 NM_001370165.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.38

Genes affected

SYTL4 (HGNC:15588): (synaptotagmin like 4) This gene encodes a member of the synaptotagmin like protein family. Members of this family are characterized by an N-terminal Rab27 binding domain and C-terminal tandem C2 domains. The encoded protein binds specific small Rab GTPases and is involved in intracellular membrane trafficking. This protein binds Rab27 and may be involved in inhibiting dense core vesicle exocytosis. Alternate splicing results in multiple transcript variants that encode the same protein. [provided by RefSeq, Mar 2010]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYTL4	NM_001370165.1	c.1352G>C	p.Arg451Pro	missense_variant	Exon 16 of 20	ENST00000372989.6	NP_001357094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYTL4	ENST00000372989.6	c.1352G>C	p.Arg451Pro	missense_variant	Exon 16 of 20	1	NM_001370165.1	ENSP00000362080.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096582 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 1 AN XY: 362032

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000186

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;T;T
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.88	.;D;.
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Pathogenic	2.9	M;M;M
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.0	D;D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0020	D;D;D
Sift4G	Benign	0.090	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.88
MutPred		0.71		Loss of catalytic residue at R451 (P = 0.0104);Loss of catalytic residue at R451 (P = 0.0104);Loss of catalytic residue at R451 (P = 0.0104);
MVP		0.42
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.99
gMVP		0.80

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-99941084;