rs139884576

Variant names:

• chr22-20859106-G-A
• rs139884576
• NM_004782.4:c.-5G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004782.4(SNAP29):​c.-5G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,596,848 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (22 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (26 hom.)
• Consequence: SNAP29 NM_004782.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0470

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 22-20859106-G-A is Benign according to our data. Variant chr22-20859106-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 340828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-20859106-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0103 (1566/152316) while in subpopulation AFR AF= 0.0352 (1464/41570). AF 95% confidence interval is 0.0337. There are 22 homozygotes in gnomad4. There are 761 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNAP29	NM_004782.4	c.-5G>A		5_prime_UTR_variant	Exon 1 of 5	ENST00000215730.12	NP_004773.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNAP29	ENST00000215730	c.-5G>A		5_prime_UTR_variant	Exon 1 of 5	1	NM_004782.4	ENSP00000215730.6
PI4KA	ENST00000449120.1	c.-19+17C>T		intron_variant	Intron 1 of 3	4		ENSP00000402437.1
SNAP29	ENST00000490458.1	n.26G>A		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1561 AN: 152198 Hom.: 22 Cov.: 33

Gnomad AFR AF: 0.0352

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00484

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00237 AC: 535 AN: 225384 Hom.: 6 AF XY: 0.00174 AC XY: 215 AN XY: 123790

Gnomad AFR exome AF: 0.0346

Gnomad AMR exome AF: 0.00163

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000104

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000614

Gnomad OTH exome AF: 0.000730

GnomAD4 exome AF: 0.00105 AC: 1521 AN: 1444532 Hom.: 26 Cov.: 30 AF XY: 0.000885 AC XY: 636 AN XY: 718676

Gnomad4 AFR exome AF: 0.0361

Gnomad4 AMR exome AF: 0.00217

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000527

Gnomad4 OTH exome AF: 0.00259

GnomAD4 genome AF: 0.0103 AC: 1566 AN: 152316 Hom.: 22 Cov.: 33 AF XY: 0.0102 AC XY: 761 AN XY: 74488

Gnomad4 AFR AF: 0.0352

Gnomad4 AMR AF: 0.00484

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.00486 Hom.: 3

Bravo AF: 0.0113

Asia WGS AF: 0.000867 AC: 3 AN: 3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 09, 2022

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Feb 03, 2017

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CEDNIK syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	5.6
DANN	Benign	0.80
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.1

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: rs139884576; hg19: chr22-21213394;