rs74807133

chr14-31080626-G-Achr14-31080626-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000334725.8(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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M116V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (12 hom.)
• Consequence: AP4S1 ENST00000334725.8 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0790

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 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 GnomAdExome at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AP4S1	NM_001128126.3	c.306+42G>A		intron_variant		ENST00000542754.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP4S1	ENST00000542754.7	c.306+42G>A		intron_variant		1	NM_001128126.3	P1

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 154 AN: 152130 Hom.: 1 Cov.: 32

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.: 8 AF XY: 0.00163 AC XY: 222 AN XY: 135884

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.: 12 Cov.: 31 AF XY: 0.000713 AC XY: 518 AN XY: 726948

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.: 1 Cov.: 32 AF XY: 0.00102 AC XY: 76 AN XY: 74448

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.: 2

Bravo AF: 0.00160

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00138 AC: 168

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 03, 2016	- -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Oct 23, 2023

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 17, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.65	T
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	N
LIST_S2	Benign	0.38	T;T;.
MetaRNN	Benign	0.0045	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.25	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	T
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

Other links and lift over

dbSNP: rs74807133; hg19: chr14-31549832; COSMIC: COSV53556357;