NM_001128126.3:c.-71-275A>G

Variant names:

• chr14-31065851-A-G
• rs36025583
• NM_001128126.3:c.-71-275A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 0 publications found

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]

AP4S1 Gene-Disease associations (from GenCC):

• AP-4 deficiency syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hereditary spastic paraplegia 52

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• AP4-related intellectual disability and spastic paraplegia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128126.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP4S1	NM_001128126.3	MANE Select	c.-71-275A>G		intron	N/A	NP_001121598.1	Q9Y587-1
	AP4S1	NM_007077.5		c.-71-275A>G		intron	N/A	NP_009008.2
	AP4S1	NM_001254727.2		c.-71-275A>G		intron	N/A	NP_001241656.1	Q9Y587-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP4S1	ENST00000542754.7	TSL:1 MANE Select	c.-71-275A>G		intron	N/A	ENSP00000438170.2	Q9Y587-1
	AP4S1	ENST00000334725.8	TSL:1	c.-71-275A>G		intron	N/A	ENSP00000334484.4	Q9Y587-4
	AP4S1	ENST00000313566.11	TSL:3	c.-71-275A>G		intron	N/A	ENSP00000322508.8	A0A8C8KCP6

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

African (AFR) AF: 0.750 AC: 30997 AN: 41354

American (AMR) AF: 0.813 AC: 12379 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.813 AC: 2822 AN: 3472

East Asian (EAS) AF: 0.540 AC: 2777 AN: 5142

South Asian (SAS) AF: 0.678 AC: 3259 AN: 4806

European-Finnish (FIN) AF: 0.831 AC: 8739 AN: 10520

Middle Eastern (MID) AF: 0.779 AC: 229 AN: 294

European-Non Finnish (NFE) AF: 0.788 AC: 53558 AN: 67934

Other (OTH) AF: 0.758 AC: 1591 AN: 2100

Alfa AF: 0.687 Hom.: 1373

Bravo AF: 0.771

Asia WGS AF: 0.625 AC: 2173 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.17
DANN	Benign	0.095
PhyloP100		-2.7
PromoterAI		-0.012	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs36025583; hg19: chr14-31535057;