22-20859043-A-T

Variant names:

• chr22-20859043-A-T
• rs117593372
• NM_004782.4:c.-68A>T

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.-68A>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 0.00586 in 1,430,268 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0059 (63 hom.)
• Consequence: SNAP29 NM_004782.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.36

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=-0.72).
• BP6: Variant 22-20859043-A-T is Benign according to our data. Variant chr22-20859043-A-T is described in ClinVar as [Benign]. Clinvar id is 340823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00583 (887/152184) while in subpopulation EAS AF= 0.054 (279/5164). AF 95% confidence interval is 0.0488. There are 7 homozygotes in gnomad4. There are 416 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNAP29	NM_004782.4	c.-68A>T		5_prime_UTR_variant	Exon 1 of 5	ENST00000215730.12	NP_004773.1
PI4KA	NM_058004.4	c.-318T>A		upstream_gene_variant		ENST00000255882.11	NP_477352.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNAP29	ENST00000215730	c.-68A>T		5_prime_UTR_variant	Exon 1 of 5	1	NM_004782.4	ENSP00000215730.6
PI4KA	ENST00000255882.11	c.-318T>A		upstream_gene_variant		1	NM_058004.4	ENSP00000255882.6

Frequencies

GnomAD3 genomes AF: 0.00586 AC: 891 AN: 152070 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00215

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00767

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0543

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.00525

Gnomad OTH AF: 0.00621

GnomAD4 exome AF: 0.00586 AC: 7494 AN: 1278084 Hom.: 63 Cov.: 20 AF XY: 0.00584 AC XY: 3732 AN XY: 638628

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00392

Gnomad4 ASJ exome AF: 0.000499

Gnomad4 EAS exome AF: 0.0454

Gnomad4 SAS exome AF: 0.00183

Gnomad4 FIN exome AF: 0.00167

Gnomad4 NFE exome AF: 0.00524

Gnomad4 OTH exome AF: 0.00637

GnomAD4 genome AF: 0.00583 AC: 887 AN: 152184 Hom.: 7 Cov.: 32 AF XY: 0.00559 AC XY: 416 AN XY: 74436

Gnomad4 AFR AF: 0.00214

Gnomad4 AMR AF: 0.00759

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0540

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00170

Gnomad4 NFE AF: 0.00525

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00168 Hom.: 0

Bravo AF: 0.00651

Asia WGS AF: 0.0150 AC: 52 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.75
DANN	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs117593372; hg19: chr22-21213331;