6-83560905-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001242792.2(SNAP91):c.2485G>A(p.Gly829Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000412 in 1,613,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000086 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00045 (0 hom.)
• Consequence: SNAP91 NM_001242792.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.83

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18816695).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNAP91	NM_001242792.2	c.2485G>A	p.Gly829Arg	missense_variant	27/30	ENST00000369694.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNAP91	ENST00000369694.7	c.2485G>A	p.Gly829Arg	missense_variant	27/30	5	NM_001242792.2	P4

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152034 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000129 AC: 32 AN: 248594 Hom.: 0 AF XY: 0.000156 AC XY: 21 AN XY: 134872

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000240

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000446 AC: 652 AN: 1461376 Hom.: 0 Cov.: 30 AF XY: 0.000432 AC XY: 314 AN XY: 726978

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000896

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000568

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.0000855 AC: 13 AN: 152034 Hom.: 0 Cov.: 33 AF XY: 0.0000539 AC XY: 4 AN XY: 74244

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000196 Hom.: 0

Bravo AF: 0.000125

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000258 AC: 1

ESP6500EA AF: 0.000241 AC: 2

ExAC AF: 0.000108 AC: 13

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

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

Jun 11, 2021

The c.2485G>A (p.G829R) alteration is located in exon 27 (coding exon 26) of the SNAP91 gene. This alteration results from a G to A substitution at nucleotide position 2485, causing the glycine (G) at amino acid position 829 to be replaced by an arginine (R). 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	0.30
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.21
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.025	T;T;T;T;T;.;.;.
Eigen	Benign	-0.084
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.72	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.1	N;N;N;N;N;N;N;N
REVEL	Benign	0.16
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.021	D;D;D;D;D;D;T;D
Polyphen		1.0	.;D;.;D;D;.;D;.
Vest4		0.76
MutPred		0.17		.;Gain of solvent accessibility (P = 0.0097);.;Gain of solvent accessibility (P = 0.0097);Gain of solvent accessibility (P = 0.0097);.;.;.;
MVP		0.71
MPC		0.64
ClinPred		0.068	T
GERP RS		3.7
Varity_R		0.13
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs369361483; hg19: chr6-84270624; COSMIC: COSV52132961;