Variant rs755820725 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.74

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP4S1	NM_001128126.3 linkuse as main transcript	c.2T>A	p.Met1?	start_lost	2/6	ENST00000542754.7	NP_001121598.1	Q9Y587-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP4S1	ENST00000542754.7 linkuse as main transcript	c.2T>A	p.Met1?	start_lost	2/6	1	NM_001128126.3	ENSP00000438170.2		Q9Y587-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251148

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135838

show subpopulations

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:

AN:

1461602

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727116

show subpopulations

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.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.42

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.54

.;D;D;.;T;.;.;D;.;.;D

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

D;.;.;D;D;D;.;D;D;.;D

M_CAP

Benign

0.014

MetaRNN

Pathogenic

0.90

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.024

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over