Genetic Variant NM_018347.3:c.296G>C (chr20-3823990-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_018347.3(AP5S1):c.296G>C(p.Arg99Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign 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. R99H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

AP5S1
NM_018347.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.40

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.37886614).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018347.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AP5S1	NM_018347.3	MANE Select	c.296G>C	p.Arg99Pro	missense	Exon 3 of 3	NP_060817.1	Q9NUS5
AP5S1	NM_001204446.2		c.296G>C	p.Arg99Pro	missense	Exon 3 of 3	NP_001191375.1	Q9NUS5
AP5S1	NM_001204447.2		c.296G>C	p.Arg99Pro	missense	Exon 3 of 3	NP_001191376.1	Q9NUS5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AP5S1	ENST00000615891.2	TSL:1 MANE Select	c.296G>C	p.Arg99Pro	missense	Exon 3 of 3	ENSP00000481750.1	Q9NUS5
AP5S1	ENST00000379573.6	TSL:1	c.*112G>C		3_prime_UTR	Exon 3 of 3	ENSP00000368892.2	Q5JX74
AP5S1	ENST00000379567.6	TSL:2	c.296G>C	p.Arg99Pro	missense	Exon 3 of 3	ENSP00000368886.2	Q9NUS5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

249908

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1460280

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726534

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51882

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111980

Other (OTH)

AF:

0.00

AC:

AN:

60382

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000166

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.030

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

Eigen

Benign

0.16

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.72

M_CAP

Benign

0.010

MetaRNN

Benign

0.38

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.8

PhyloP100

2.4

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-3.9

REVEL

Benign

0.20

Sift

Benign

0.036

Sift4G

Uncertain

0.058

Polyphen

0.98

Vest4

0.50

MutPred

0.30

Loss of helix (P = 0.0104)

MVP

0.22

MPC

0.26

ClinPred

0.97

GERP RS

3.0

Varity_R

0.72

gMVP

0.82

Mutation Taster

=80/20

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over