chr2-223777778-G-A

Position:

• chr2-223777778-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001039569.2(AP1S3):​c.95C>T​(p.Thr32Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00516 in 1,614,086 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0041 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0053 (21 hom.)
• Consequence: AP1S3 NM_001039569.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:4
• Conservation: PhyloP100: 1.05

Genes affected

AP1S3 (HGNC:18971): (adaptor related protein complex 1 subunit sigma 3) This gene encodes a member of the adaptor-related protein complex 1, sigma subunit genes. The encoded protein is a component of adaptor protein complex 1 (AP-1), one of the AP complexes involved in claathrin-mediated vesicular transport from the Golgi or endosomes. Disruption of the pathway for display of HIV-1 antigens, which prevents recognition of the virus by cytotoxic T cells, has been shown to involve the AP-1 complex (PMID: 15569716). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010055482).
• BP6: Variant 2-223777778-G-A is Benign according to our data. Variant chr2-223777778-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1206126.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-223777778-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 618 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AP1S3	NM_001039569.2	c.95C>T	p.Thr32Ile	missense_variant	2/5	ENST00000396654.7
AP1S3	XM_011510600.4	c.95C>T	p.Thr32Ile	missense_variant	2/4
AP1S3	NR_110905.2	n.227C>T		non_coding_transcript_exon_variant	2/6
AP1S3	NR_110906.2	n.227C>T		non_coding_transcript_exon_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP1S3	ENST00000396654.7	c.95C>T	p.Thr32Ile	missense_variant	2/5	2	NM_001039569.2	P1

Frequencies

GnomAD3 genomes AF: 0.00406 AC: 618 AN: 152172 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00700

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00635

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00354 AC: 884 AN: 249476 Hom.: 3 AF XY: 0.00332 AC XY: 450 AN XY: 135356

Gnomad AFR exome AF: 0.00110

Gnomad AMR exome AF: 0.00432

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00130

Gnomad NFE exome AF: 0.00582

Gnomad OTH exome AF: 0.00396

GnomAD4 exome AF: 0.00527 AC: 7703 AN: 1461796 Hom.: 21 Cov.: 31 AF XY: 0.00502 AC XY: 3648 AN XY: 727210

Gnomad4 AFR exome AF: 0.000807

Gnomad4 AMR exome AF: 0.00427

Gnomad4 ASJ exome AF: 0.000536

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00120

Gnomad4 NFE exome AF: 0.00643

Gnomad4 OTH exome AF: 0.00422

GnomAD4 genome AF: 0.00406 AC: 618 AN: 152290 Hom.: 4 Cov.: 33 AF XY: 0.00353 AC XY: 263 AN XY: 74454

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.00699

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00635

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.00564 Hom.: 5

Bravo AF: 0.00412

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.000270 AC: 1

ESP6500EA AF: 0.00697 AC: 57

ExAC AF: 0.00345 AC: 417

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00714

EpiControl AF: 0.00670

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	AP1S3: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	17
DANN	Benign	0.71
DEOGEN2	Benign	0.034	.;.;T;T;T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.85	D;D;D;D;D
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.010	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.67	N;N;.;N;.
MutationTaster	Benign	0.73	N;N;N;N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.7	D;D;D;D;N
REVEL	Benign	0.090
Sift	Benign	0.65	T;T;T;T;T
Sift4G	Benign	0.54	T;T;T;T;T
Polyphen		0.0	.;B;.;B;.
Vest4		0.72
MVP		0.15
MPC		0.065
ClinPred		0.032	T
GERP RS		4.1
Varity_R		0.22
gMVP		0.12

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: rs78536455; hg19: chr2-224642495; COSMIC: COSV100525188;