14-31065851-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001128126.3(AP4S1):c.-71-275A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.772 in 151,762 control chromosomes in the GnomAD database, including 45,440 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.77 (45440 hom., cov: 29)
• Consequence: AP4S1 NM_001128126.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.66

Genes affected

AP4S1 (HGNC:575): (adaptor related protein complex 4 subunit sigma 1) This gene encodes a member of the adaptor complexes small subunit protein family. These proteins are components of the heterotetrameric adaptor protein complexes, which play important roles in the secretory and endocytic pathways by mediating vesicle formation and sorting of integral membrane proteins. The encoded protein is the small subunit of adaptor protein complex-4, which is associated with both clathrin- and nonclathrin-coated vesicles. Mutations in this gene are associated with spastic quadriplegic cerebral palsy-6. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 6. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.04).
• BP6: Variant 14-31065851-A-G is Benign according to our data. Variant chr14-31065851-A-G is described in ClinVar as [Benign]. Clinvar id is 669811.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.801 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AP4S1	NM_001128126.3	c.-71-275A>G		intron_variant		ENST00000542754.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP4S1	ENST00000542754.7	c.-71-275A>G		intron_variant		1	NM_001128126.3	P1

Frequencies

GnomAD3 genomes AF: 0.772 AC: 117056 AN: 151644 Hom.: 45407 Cov.: 29

Gnomad AFR AF: 0.750

Gnomad AMI AF: 0.866

Gnomad AMR AF: 0.812

Gnomad ASJ AF: 0.813

Gnomad EAS AF: 0.540

Gnomad SAS AF: 0.680

Gnomad FIN AF: 0.831

Gnomad MID AF: 0.788

Gnomad NFE AF: 0.788

Gnomad OTH AF: 0.757

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.772 AC: 117136 AN: 151762 Hom.: 45440 Cov.: 29 AF XY: 0.772 AC XY: 57259 AN XY: 74156

Gnomad4 AFR AF: 0.750

Gnomad4 AMR AF: 0.813

Gnomad4 ASJ AF: 0.813

Gnomad4 EAS AF: 0.540

Gnomad4 SAS AF: 0.678

Gnomad4 FIN AF: 0.831

Gnomad4 NFE AF: 0.788

Gnomad4 OTH AF: 0.758

Alfa AF: 0.687 Hom.: 1373

Bravo AF: 0.771

Asia WGS AF: 0.625 AC: 2173 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
Cadd	Benign	0.17
Dann	Benign	0.095

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: rs36025583; hg19: chr14-31535057;