20-3823915-G-A

Position:

• chr20-3823915-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018347.3(AP5S1):​c.221G>A​(p.Arg74Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000345 in 1,451,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: AP5S1 NM_018347.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.31

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13677621).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AP5S1	NM_018347.3	c.221G>A	p.Arg74Gln	missense_variant	3/3	ENST00000615891.2
AP5S1	NM_001204446.2	c.221G>A	p.Arg74Gln	missense_variant	3/3
AP5S1	NM_001204447.2	c.221G>A	p.Arg74Gln	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP5S1	ENST00000615891.2	c.221G>A	p.Arg74Gln	missense_variant	3/3	1	NM_018347.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000345 AC: 5 AN: 1451144 Hom.: 0 Cov.: 32 AF XY: 0.00000415 AC XY: 3 AN XY: 722144

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

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: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2023

The c.221G>A (p.R74Q) alteration is located in exon 3 (coding exon 2) of the AP5S1 gene. This alteration results from a G to A substitution at nucleotide position 221, causing the arginine (R) at amino acid position 74 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Oct 04, 2023

Gene of Uncertain Significance -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T;T;T
Eigen	Benign	-0.084
Eigen_PC	Benign	-0.089
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	D;.;T;.
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.1	M;M;.;M
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.8	N;N;D;.
REVEL	Benign	0.082
Sift	Benign	0.062	T;T;T;.
Sift4G	Benign	0.095	T;T;T;T
Polyphen		0.88	P;P;.;P
Vest4		0.076
MutPred		0.23		Loss of MoRF binding (P = 0.0408);Loss of MoRF binding (P = 0.0408);Loss of MoRF binding (P = 0.0408);Loss of MoRF binding (P = 0.0408);
MVP		0.067
MPC		0.067
ClinPred		0.70	D
GERP RS		4.1
Varity_R		0.13
gMVP		0.49

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: rs994202221; hg19: chr20-3804562; COSMIC: COSV55694471; COSMIC: COSV55694471;