20-3823890-C-G

Variant names:

• chr20-3823890-C-G
• rs367607495
• NM_018347.3:c.196C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018347.3(AP5S1):​c.196C>G​(p.Arg66Gly) 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. 16/21 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. R66W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AP5S1 NM_018347.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.157
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03575939).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP5S1	NM_018347.3	MANE Select	c.196C>G	p.Arg66Gly	missense	Exon 3 of 3	NP_060817.1	Q9NUS5
	AP5S1	NM_001204446.2		c.196C>G	p.Arg66Gly	missense	Exon 3 of 3	NP_001191375.1	Q9NUS5
	AP5S1	NM_001204447.2		c.196C>G	p.Arg66Gly	missense	Exon 3 of 3	NP_001191376.1	Q9NUS5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP5S1	ENST00000615891.2	TSL:1 MANE Select	c.196C>G	p.Arg66Gly	missense	Exon 3 of 3	ENSP00000481750.1	Q9NUS5
	AP5S1	ENST00000379573.6	TSL:1	c.*12C>G		3_prime_UTR	Exon 3 of 3	ENSP00000368892.2	Q5JX74
	AP5S1	ENST00000379567.6	TSL:2	c.196C>G	p.Arg66Gly	missense	Exon 3 of 3	ENSP00000368886.2	Q9NUS5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.16
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.15
Sift	Benign	0.31	T
Sift4G	Benign	0.38	T
Polyphen		0.065	B
Vest4		0.10
MutPred		0.20		Loss of MoRF binding (P = 0.003)
MVP		0.095
MPC		0.095
ClinPred		0.083	T
GERP RS		2.8
Varity_R		0.087
gMVP		0.27
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs367607495; hg19: chr20-3804537;