NM_018347.3:c.385C>G

Variant names:

• chr20-3824079-C-G
• NM_018347.3:c.385C>G

Variant summary

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

The NM_018347.3(AP5S1):​c.385C>G​(p.His129Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AP5S1 NM_018347.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.71

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP5S1	NM_018347.3	c.385C>G	p.His129Asp	missense_variant	Exon 3 of 3	ENST00000615891.2	NP_060817.1
AP5S1	NM_001204446.2	c.385C>G	p.His129Asp	missense_variant	Exon 3 of 3		NP_001191375.1
AP5S1	NM_001204447.2	c.385C>G	p.His129Asp	missense_variant	Exon 3 of 3		NP_001191376.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP5S1	ENST00000615891.2	c.385C>G	p.His129Asp	missense_variant	Exon 3 of 3	1	NM_018347.3	ENSP00000481750.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.385C>G (p.H129D) alteration is located in exon 3 (coding exon 2) of the AP5S1 gene. This alteration results from a C to G substitution at nucleotide position 385, causing the histidine (H) at amino acid position 129 to be replaced by an aspartic acid (D). 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	0.12
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;T;T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.63	T;.;.
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.44	T;T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.4	M;M;M
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.5	D;D;.
REVEL	Benign	0.25
Sift	Uncertain	0.017	D;D;.
Sift4G	Uncertain	0.041	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.51
MutPred		0.55		Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);
MVP		0.17
MPC		0.26
ClinPred		0.90	D
GERP RS		5.7
Varity_R		0.45
gMVP		0.69

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-3804726;