rs568176223

chr14-31072908-G-Achr14-31072908-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001128126.3(AP4S1):c.229G>A(p.Glu77Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,612,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: AP4S1 NM_001128126.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.97

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.783

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AP4S1	NM_001128126.3	c.229G>A	p.Glu77Lys	missense_variant	4/6	ENST00000542754.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP4S1	ENST00000542754.7	c.229G>A	p.Glu77Lys	missense_variant	4/6	1	NM_001128126.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152080 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251356 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135870

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1459972 Hom.: 0 Cov.: 30 AF XY: 0.0000193 AC XY: 14 AN XY: 726444

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74424

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2023

The c.229G>A (p.E77K) alteration is located in exon 4 (coding exon 3) of the AP4S1 gene. This alteration results from a G to A substitution at nucleotide position 229, causing the glutamic acid (E) at amino acid position 77 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;.;.;D;D;D;.;D;D;D;D
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.24	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.8	D;.;D;D;D;D;D;D;D;.;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0040	D;.;D;D;D;D;D;D;D;.;D
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 1.0	.;D;D;.;.;D;.;.;.;D;.
Vest4		0.82, 0.83, 0.86, 0.85, 0.88, 0.86
MutPred		0.73		Gain of catalytic residue at D73 (P = 0.0057);Gain of catalytic residue at D73 (P = 0.0057);Gain of catalytic residue at D73 (P = 0.0057);Gain of catalytic residue at D73 (P = 0.0057);Gain of catalytic residue at D73 (P = 0.0057);Gain of catalytic residue at D73 (P = 0.0057);Gain of catalytic residue at D73 (P = 0.0057);Gain of catalytic residue at D73 (P = 0.0057);Gain of catalytic residue at D73 (P = 0.0057);Gain of catalytic residue at D73 (P = 0.0057);.;
MVP		0.47
MPC		0.58
ClinPred		0.81	D
GERP RS		5.5
Varity_R		0.92
gMVP		0.74

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: rs568176223; hg19: chr14-31542114; COSMIC: COSV53555732;