Variant 20-3823935-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_018347.3(AP5S1):c.241C>T(p.Pro81Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,606,056 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

AP5S1
NM_018347.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0220

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.026228637).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
AP5S1	NM_018347.3 linkuse as main transcript	c.241C>T	p.Pro81Ser	missense_variant	3/3	ENST00000615891.2	NP_060817.1
AP5S1	NM_001204446.2 linkuse as main transcript	c.241C>T	p.Pro81Ser	missense_variant	3/3		NP_001191375.1
AP5S1	NM_001204447.2 linkuse as main transcript	c.241C>T	p.Pro81Ser	missense_variant	3/3		NP_001191376.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP5S1	ENST00000615891.2 linkuse as main transcript	c.241C>T	p.Pro81Ser	missense_variant	3/3	1	NM_018347.3	ENSP00000481750	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000123

AC:

AN:

243688

Hom.:

AF XY:

0.0000226

AC XY:

AN XY:

132758

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000117

AC:

AN:

1453836

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

723566

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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

Nov 03, 2022

The c.241C>T (p.P81S) alteration is located in exon 3 (coding exon 2) of the AP5S1 gene. This alteration results from a C to T substitution at nucleotide position 241, causing the proline (P) at amino acid position 81 to be replaced by a serine (S). 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

Benign

0.075

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.48

CADD

Benign

8.0

DANN

Benign

0.73

DEOGEN2

Benign

0.0070

T;T;T;T

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.55

T;.;T;.

M_CAP

Benign

0.0048

MetaRNN

Benign

0.026

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.2

M;M;.;M

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.71

N;N;N;.

REVEL

Benign

0.029

Sift

Benign

0.86

T;T;T;.

Sift4G

Benign

0.41

T;T;T;T

Polyphen

0.024

B;B;.;B

Vest4

0.034

MutPred

0.14

Gain of phosphorylation at P81 (P = 0.0331);Gain of phosphorylation at P81 (P = 0.0331);Gain of phosphorylation at P81 (P = 0.0331);Gain of phosphorylation at P81 (P = 0.0331);

MVP

0.048

MPC

0.058

ClinPred

0.035

GERP RS

0.70

Varity_R

0.025

gMVP

0.33

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