5-141656240-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_022481.6(ARAP3):c.3826G>T(p.Ala1276Ser) 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. 15/21 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)
• Consequence: ARAP3 NM_022481.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.99

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29883528).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARAP3	NM_022481.6	c.3826G>T	p.Ala1276Ser	missense_variant	28/33	ENST00000239440.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARAP3	ENST00000239440.9	c.3826G>T	p.Ala1276Ser	missense_variant	28/33	1	NM_022481.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

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

Jan 19, 2024

The c.3826G>T (p.A1276S) alteration is located in exon 28 (coding exon 27) of the ARAP3 gene. This alteration results from a G to T substitution at nucleotide position 3826, causing the alanine (A) at amino acid position 1276 to be replaced by a serine (S). 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	0.16
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.26	T;T;T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	0.0055
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.30	T;T;T;T
MetaSVM	Benign	-0.48	T
MutationTaster	Benign	0.53	D;D;D;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.2	N;N;.;N
REVEL	Benign	0.13
Sift	Benign	0.077	T;T;.;T
Sift4G	Uncertain	0.053	T;D;T;D
Polyphen		0.0010	B;B;B;.
Vest4		0.27
MutPred		0.71		.;Gain of disorder (P = 0.0136);.;.;
MVP		0.58
MPC		0.32
ClinPred		0.73	D
GERP RS		4.6
Varity_R		0.092
gMVP		0.42

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: chr5-141035807;