Variant 20-3822179-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018347.3(AP5S1):c.62G>A(p.Cys21Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

AP5S1
NM_018347.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.73

Variant links:

Genes affected

AP5S1 (HGNC:15875): (adaptor related protein complex 5 subunit sigma 1) Involved in double-strand break repair via homologous recombination and endosomal transport. Located in several cellular components, including late endosome; lysosome; and nucleoplasm. Part of AP-type membrane coat adaptor complex. [provided by Alliance of Genome Resources, Apr 2022]

AP5S1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
AP5S1	NM_018347.3 linkuse as main transcript	c.62G>A	p.Cys21Tyr	missense_variant	2/3	ENST00000615891.2	NP_060817.1
AP5S1	NM_001204446.2 linkuse as main transcript	c.62G>A	p.Cys21Tyr	missense_variant	2/3		NP_001191375.1
AP5S1	NM_001204447.2 linkuse as main transcript	c.62G>A	p.Cys21Tyr	missense_variant	2/3		NP_001191376.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP5S1	ENST00000615891.2 linkuse as main transcript	c.62G>A	p.Cys21Tyr	missense_variant	2/3	1	NM_018347.3	ENSP00000481750	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251408

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2022

The c.62G>A (p.C21Y) alteration is located in exon 2 (coding exon 1) of the AP5S1 gene. This alteration results from a G to A substitution at nucleotide position 62, causing the cysteine (C) at amino acid position 21 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.36

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.15

T;.;T;T;T

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.78

T;T;.;T;.

M_CAP

Benign

0.013

MetaRNN

Uncertain

0.65

D;D;D;D;D

MetaSVM

Benign

-0.29

MutationAssessor

Uncertain

2.1

M;.;M;.;M

MutationTaster

Benign

0.98

D;D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-3.7

D;D;D;D;.

REVEL

Uncertain

0.38

Sift

Uncertain

0.0040

D;D;D;D;.

Sift4G

Uncertain

0.013

D;D;D;D;D

Polyphen

1.0

D;.;D;.;D

Vest4

0.88

MutPred

0.53

Loss of catalytic residue at V23 (P = 0.0817);Loss of catalytic residue at V23 (P = 0.0817);Loss of catalytic residue at V23 (P = 0.0817);Loss of catalytic residue at V23 (P = 0.0817);Loss of catalytic residue at V23 (P = 0.0817);

MVP

0.23

MPC

0.46

ClinPred

0.97

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.43

gMVP

0.59

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