6-83576053-T-C

Position:

• chr6-83576053-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001242792.2(SNAP91):​c.2300A>G​(p.Asn767Ser) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SNAP91 NM_001242792.2 missense, splice_region
• Scores: Splicing: ADA: 0.5030
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.19

Genes affected

SNAP91 (HGNC:14986): (synaptosome associated protein 91) Predicted to enable several functions, including SNARE binding activity; clathrin binding activity; and phosphatidylinositol binding activity. Acts upstream of or within regulation of clathrin-dependent endocytosis. Predicted to be located in several cellular components, including postsynaptic density; presynaptic endosome; and presynaptic membrane. Predicted to be extrinsic component of endosome membrane. Predicted to be active in several cellular components, including Schaffer collateral - CA1 synapse; cytoplasmic vesicle; and parallel fiber to Purkinje cell synapse. Predicted to be extrinsic component of presynaptic endocytic zone membrane. Biomarker of Alzheimer's disease. [provided by Alliance of Genome Resources, Apr 2022]

SNAP91 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SNAP91	NM_001242792.2	c.2300A>G	p.Asn767Ser	missense_variant, splice_region_variant	25/30	ENST00000369694.7	NP_001229721.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SNAP91	ENST00000369694.7	c.2300A>G	p.Asn767Ser	missense_variant, splice_region_variant	25/30	5	NM_001242792.2	ENSP00000358708.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1223448 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 610748

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 26, 2024

The c.2300A>G (p.N767S) alteration is located in exon 25 (coding exon 24) of the SNAP91 gene. This alteration results from a A to G substitution at nucleotide position 2300, causing the asparagine (N) at amino acid position 767 to be replaced by a serine (S). 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	Benign	0.16
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T;T;T;T;.;.;.;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	.;.;D;.;D;D;D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.46	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Pathogenic	3.0	.;M;.;M;M;.;.;.;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.4	D;D;D;D;D;D;D;D;D
REVEL	Benign	0.17
Sift	Benign	0.033	D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.10	T;T;T;T;T;T;T;D;.
Polyphen		0.87, 0.99	.;P;.;P;P;.;D;.;.
Vest4		0.73
MutPred		0.37		.;Loss of helix (P = 0.0104);.;Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);.;.;.;.;
MVP		0.62
MPC		0.52
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.26
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.50
dbscSNV1_RF	Benign	0.53
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: rs994699103; hg19: chr6-84285772;