NM_001128126.3:c.-71-6260G>C

Variant names:

• chr14-31059866-G-C
• rs17449560
• NM_001128126.3:c.-71-6260G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001128126.3(AP4S1):​c.-71-6260G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0883 in 151,274 control chromosomes in the GnomAD database, including 674 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.088 (674 hom., cov: 31)
• Consequence: AP4S1 NM_001128126.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0880
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.145 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP4S1	NM_001128126.3	c.-71-6260G>C		intron_variant	Intron 1 of 5	ENST00000542754.7	NP_001121598.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP4S1	ENST00000542754.7	c.-71-6260G>C		intron_variant	Intron 1 of 5	1	NM_001128126.3	ENSP00000438170.2

Frequencies

GnomAD3 genomes AF: 0.0884 AC: 13356 AN: 151170 Hom.: 675 Cov.: 31

Gnomad AFR AF: 0.0526

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.0881

Gnomad ASJ AF: 0.100

Gnomad EAS AF: 0.0168

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.115

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.0893

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

GnomAD4 genome AF: 0.0883 AC: 13365 AN: 151274 Hom.: 674 Cov.: 31 AF XY: 0.0896 AC XY: 6616 AN XY: 73846

African (AFR) AF: 0.0530 AC: 2188 AN: 41314

American (AMR) AF: 0.0879 AC: 1326 AN: 15088

Ashkenazi Jewish (ASJ) AF: 0.100 AC: 347 AN: 3468

East Asian (EAS) AF: 0.0169 AC: 87 AN: 5154

South Asian (SAS) AF: 0.155 AC: 742 AN: 4796

European-Finnish (FIN) AF: 0.117 AC: 1204 AN: 10292

Middle Eastern (MID) AF: 0.110 AC: 32 AN: 290

European-Non Finnish (NFE) AF: 0.106 AC: 7198 AN: 67866

Other (OTH) AF: 0.0898 AC: 188 AN: 2094

Alfa AF: 0.0985 Hom.: 95

Bravo AF: 0.0810

Asia WGS AF: 0.0880 AC: 307 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.7
DANN	Benign	0.62
PhyloP100		0.088
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: rs17449560; hg19: chr14-31529072;