rs74807133

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_007077.5(AP4S1):c.348G>A(p.Met116Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000721 in 1,613,440 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0010 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00069 ( 12 hom. )

Consequence

AP4S1
NM_007077.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.0790

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004475653).

BP6

Variant 14-31080626-G-A is Benign according to our data. Variant chr14-31080626-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 210219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-31080626-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00102 (155/152248) while in subpopulation EAS AF= 0.0137 (71/5182). AF 95% confidence interval is 0.0111. There are 1 homozygotes in gnomad4. There are 76 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP4S1	NM_001128126.3 linkuse as main transcript	c.306+42G>A		intron_variant		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.306+42G>A		intron_variant		1	NM_001128126.3	ENSP00000438170.2		Q9Y587-1

Frequencies

GnomAD3 genomes

AF:

0.00101

AC:

154

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00295

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.0135

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00159

AC:

399

AN:

251374

Hom.:

AF XY:

0.00163

AC XY:

222

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000636

Gnomad ASJ exome

AF:

0.00218

Gnomad EAS exome

AF:

0.0167

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000237

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.000690

AC:

1008

AN:

1461192

Hom.:

Cov.:

AF XY:

0.000713

AC XY:

518

AN XY:

726948

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00103

Gnomad4 ASJ exome

AF:

0.00199

Gnomad4 EAS exome

AF:

0.0144

Gnomad4 SAS exome

AF:

0.000197

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.000211

Gnomad4 OTH exome

AF:

0.00128

GnomAD4 genome

AF:

0.00102

AC:

155

AN:

152248

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00295

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.0137

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000441

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000864

Hom.:

Bravo

AF:

0.00160

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00138

AC:

168

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 03, 2016	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 17, 2015

- -

Spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 23, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.69

CADD

Benign

1.2

DANN

Benign

0.50

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.00044

LIST_S2

Benign

0.38

T;T;.

MetaRNN

Benign

0.0045

T;T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.25

PROVEAN

Benign

0.75

.;N;N

REVEL

Benign

0.049

Sift

Benign

0.030

.;D;T

Sift4G

Benign

0.32

T;T;T

Polyphen

0.0

.;B;.

Vest4

0.18

MutPred

0.48

Gain of catalytic residue at Q115 (P = 0.0032);Gain of catalytic residue at Q115 (P = 0.0032);Gain of catalytic residue at Q115 (P = 0.0032);

MVP

0.076

MPC

0.14

ClinPred

0.021

GERP RS

-4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.26

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over