rs755820725

chr14-31066198-T-Achr14-31066198-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate PM2

The NM_001128126.3(AP4S1):c.2T>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000205 in 1,461,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: AP4S1 NM_001128126.3 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.74

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_001128126.3 (AP4S1) was described as [Likely_pathogenic] in ClinVar as 520786
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AP4S1	NM_001128126.3	c.2T>A	p.Met1?	start_lost	2/6	ENST00000542754.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP4S1	ENST00000542754.7	c.2T>A	p.Met1?	start_lost	2/6	1	NM_001128126.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251148 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135838

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461602 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727116

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Uncertain	25
Dann	Uncertain	0.99
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D;.;.;D;D;D;.;D;D;.;D
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.024	D
MutationTaster	Benign	0.98	D;D;D;D;D;D
PROVEAN	Pathogenic	-4.6	D;.;D;D;D;D;D;D;D;D;.
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D;.;D;D;D;D;D;D;D;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;.;D
Polyphen		1.0, 0.99	.;D;D;.;.;D;.;.;.;.;D
Vest4		0.96, 0.93, 0.93, 0.93, 0.95, 0.91
MutPred		0.74		Gain of disorder (P = 0.0092);Gain of disorder (P = 0.0092);Gain of disorder (P = 0.0092);Gain of disorder (P = 0.0092);Gain of disorder (P = 0.0092);Gain of disorder (P = 0.0092);Gain of disorder (P = 0.0092);Gain of disorder (P = 0.0092);Gain of disorder (P = 0.0092);Gain of disorder (P = 0.0092);Gain of disorder (P = 0.0092);
MVP		0.51
ClinPred		0.94	D
GERP RS		6.0
Varity_R		0.93
gMVP		0.80

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: rs755820725; hg19: chr14-31535404;