22-20859092-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004782.4(SNAP29):c.-19C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.542 in 1,574,152 control chromosomes in the GnomAD database, including 233,853 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (19890 hom., cov: 33)
  • Exomes 𝑓: 0.55 (213963 hom.)
• Consequence: SNAP29 NM_004782.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.54

Genes affected

SNAP29 (HGNC:11133): (synaptosome associated protein 29) This gene, a member of the SNAP25 gene family, encodes a protein involved in multiple membrane trafficking steps. Two other members of this gene family, SNAP23 and SNAP25, encode proteins that bind a syntaxin protein and mediate synaptic vesicle membrane docking and fusion to the plasma membrane. The protein encoded by this gene binds tightly to multiple syntaxins and is localized to intracellular membrane structures rather than to the plasma membrane. While the protein is mostly membrane-bound, a significant fraction of it is found free in the cytoplasm. Use of multiple polyadenylation sites has been noted for this gene. [provided by RefSeq, Jul 2008]

PI4KA (HGNC:8983): (phosphatidylinositol 4-kinase alpha) This gene encodes a phosphatidylinositol (PI) 4-kinase which catalyzes the first committed step in the biosynthesis of phosphatidylinositol 4,5-bisphosphate. The mammalian PI 4-kinases have been classified into two types, II and III, based on their molecular mass, and modulation by detergent and adenosine. The protein encoded by this gene is a type III enzyme that is not inhibited by adenosine. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Apr 2018]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 22-20859092-C-T is Benign according to our data. Variant chr22-20859092-C-T is described in ClinVar as [Benign]. Clinvar id is 340826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-20859092-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNAP29	NM_004782.4	c.-19C>T		5_prime_UTR_variant	1/5	ENST00000215730.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNAP29	ENST00000215730.12	c.-19C>T		5_prime_UTR_variant	1/5	1	NM_004782.4	P1
PI4KA	ENST00000449120.1	c.-19+31G>A		intron_variant		4
SNAP29	ENST00000490458.1	n.12C>T		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.504 AC: 76633 AN: 151960 Hom.: 19887 Cov.: 33

Gnomad AFR AF: 0.403

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.456

Gnomad ASJ AF: 0.518

Gnomad EAS AF: 0.419

Gnomad SAS AF: 0.595

Gnomad FIN AF: 0.711

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.546

Gnomad OTH AF: 0.480

GnomAD3 exomes AF: 0.527 AC: 114504 AN: 217444 Hom.: 31128 AF XY: 0.534 AC XY: 63853 AN XY: 119502

Gnomad AFR exome AF: 0.392

Gnomad AMR exome AF: 0.409

Gnomad ASJ exome AF: 0.516

Gnomad EAS exome AF: 0.407

Gnomad SAS exome AF: 0.602

Gnomad FIN exome AF: 0.706

Gnomad NFE exome AF: 0.547

Gnomad OTH exome AF: 0.523

GnomAD4 exome AF: 0.545 AC: 775737 AN: 1422074 Hom.: 213963 Cov.: 27 AF XY: 0.548 AC XY: 387858 AN XY: 707996

Gnomad4 AFR exome AF: 0.393

Gnomad4 AMR exome AF: 0.419

Gnomad4 ASJ exome AF: 0.519

Gnomad4 EAS exome AF: 0.442

Gnomad4 SAS exome AF: 0.606

Gnomad4 FIN exome AF: 0.701

Gnomad4 NFE exome AF: 0.548

Gnomad4 OTH exome AF: 0.537

GnomAD4 genome AF: 0.504 AC: 76672 AN: 152078 Hom.: 19890 Cov.: 33 AF XY: 0.511 AC XY: 38009 AN XY: 74358

Gnomad4 AFR AF: 0.403

Gnomad4 AMR AF: 0.455

Gnomad4 ASJ AF: 0.518

Gnomad4 EAS AF: 0.419

Gnomad4 SAS AF: 0.595

Gnomad4 FIN AF: 0.711

Gnomad4 NFE AF: 0.546

Gnomad4 OTH AF: 0.482

Alfa AF: 0.528 Hom.: 13855

Bravo AF: 0.479

Asia WGS AF: 0.509 AC: 1771 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CEDNIK syndrome Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not specified Benign:1

Benign, flagged submission

clinical testing

GeneDx

Jul 06, 2015

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 20, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	4.7
Dann	Benign	0.87
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs1061063; hg19: chr22-21213380;