chr5-141658437-G-T

Position:

• chr5-141658437-G-T

Variant summary

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

The ENST00000239440.9(ARAP3):​c.3454C>A​(p.Leu1152Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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: ARAP3 ENST00000239440.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.32

Genes affected

ARAP3 (HGNC:24097): (ArfGAP with RhoGAP domain, ankyrin repeat and PH domain 3) This gene encodes a phosphoinositide binding protein containing ARF-GAP, RHO-GAP, RAS-associating, and pleckstrin homology domains. The ARF-GAP and RHO-GAP domains cooperate in mediating rearrangements in the cell cytoskeleton and cell shape. It is a specific PtdIns(3,4,5)P3/PtdIns(3,4)P2-stimulated Arf6-GAP protein. An alternatively spliced transcript has been found for this gene, but its biological validity has not been determined. [provided by RefSeq, Sep 2015]

ARAP3 (HGNC:):

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/exons	MANE	Protein	UniProt
ARAP3	NM_022481.6	c.3454C>A	p.Leu1152Met	missense_variant	25/33	ENST00000239440.9	NP_071926.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARAP3	ENST00000239440.9	c.3454C>A	p.Leu1152Met	missense_variant	25/33	1	NM_022481.6	ENSP00000239440.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2023

The c.3454C>A (p.L1152M) alteration is located in exon 25 (coding exon 24) of the ARAP3 gene. This alteration results from a C to A substitution at nucleotide position 3454, causing the leucine (L) at amino acid position 1152 to be replaced by a methionine (M). 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	0.18
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.056	T;T;T;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.92	.;D;D;D
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.50	D;D;D;D
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.1	.;M;.;.
MutationTaster	Benign	1.0	D;D;D;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.8	N;N;.;N
REVEL	Benign	0.25
Sift	Uncertain	0.019	D;D;.;D
Sift4G	Benign	0.11	T;T;T;T
Polyphen		1.0	D;D;D;.
Vest4		0.53
MutPred		0.70		.;Gain of helix (P = 0.0854);.;.;
MVP		0.42
MPC		1.0
ClinPred		0.89	D
GERP RS		4.2
Varity_R		0.25
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.30		Position offset: 4

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

Publications

LitVar

Other links and lift over

dbSNP: rs372104720; hg19: chr5-141038004;