2-223775944-A-T

Variant names:

• chr2-223775944-A-T
• NM_001039569.2:c.248T>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001039569.2(AP1S3):​c.248T>A​(p.Ile83Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,854 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I83T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: AP1S3 NM_001039569.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.22

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]

ENSG00000286239 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.855

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP1S3	NM_001039569.2	c.248T>A	p.Ile83Asn	missense_variant	Exon 3 of 5	ENST00000396654.7	NP_001034658.1
AP1S3	XM_011510600.4	c.248T>A	p.Ile83Asn	missense_variant	Exon 3 of 4		XP_011508902.1
AP1S3	NR_110905.2	n.380T>A		non_coding_transcript_exon_variant	Exon 3 of 6
AP1S3	NR_110906.2	n.314+1747T>A		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP1S3	ENST00000396654.7	c.248T>A	p.Ile83Asn	missense_variant	Exon 3 of 5	2	NM_001039569.2	ENSP00000379891.2
ENSG00000286239	ENST00000650969.1	n.*1212T>A		non_coding_transcript_exon_variant	Exon 15 of 17			ENSP00000498456.1
ENSG00000286239	ENST00000650969.1	n.*1212T>A		3_prime_UTR_variant	Exon 15 of 17			ENSP00000498456.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461854 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	.;.;T;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.9	M;M;M;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-6.3	D;D;D;D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.053	T;T;T;T
Polyphen		0.14, 0.90	.;B;P;.
Vest4		0.87
MutPred		0.59		Gain of disorder (P = 0.091);Gain of disorder (P = 0.091);Gain of disorder (P = 0.091);Gain of disorder (P = 0.091);
MVP		0.87
MPC		0.27
ClinPred		0.99	D
GERP RS		3.7
Varity_R		0.92
gMVP		0.64

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-224640661;