rs199670262

Variant names:

• chr4-36083401-C-A
• rs199670262
• NM_015230.4:c.4475G>T

Your query was ambiguous. Multiple possible variants found:

• chr4-36083401-C-A
• chr4-36083401-C-G
• chr4-36083401-C-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_015230.4(ARAP2):​c.4475G>T​(p.Arg1492Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000755 in 1,456,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1492H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: ARAP2 NM_015230.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.96
• Publications: 2 publications found

Genes affected

ARAP2 (HGNC:16924): (ArfGAP with RhoGAP domain, ankyrin repeat and PH domain 2) The protein encoded by this gene contains ARF-GAP, RHO-GAP, ankyrin repeat, RAS-associating, and pleckstrin homology domains. The protein is a phosphatidylinositol (3,4,5)-trisphosphate-dependent Arf6 GAP that binds RhoA-GTP, but it lacks the predicted catalytic arginine in the RHO-GAP domain and does not have RHO-GAP activity. The protein associates with focal adhesions and functions downstream of RhoA to regulate focal adhesion dynamics. [provided by RefSeq, Sep 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.027244389).
• BP6: Variant 4-36083401-C-A is Benign according to our data. Variant chr4-36083401-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3887869.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015230.4. 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
	ARAP2	NM_015230.4	MANE Select	c.4475G>T	p.Arg1492Leu	missense	Exon 29 of 33	NP_056045.2
	ARAP2	NR_146893.2		n.4965G>T		non_coding_transcript_exon	Exon 29 of 37
	ARAP2	NR_146894.2		n.4936G>T		non_coding_transcript_exon	Exon 29 of 33

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARAP2	ENST00000303965.9	TSL:1 MANE Select	c.4475G>T	p.Arg1492Leu	missense	Exon 29 of 33	ENSP00000302895.4	Q8WZ64
	ARAP2	ENST00000942324.1		c.4475G>T	p.Arg1492Leu	missense	Exon 29 of 33	ENSP00000612383.1
	ARAP2	ENST00000905954.1		c.4406G>T	p.Arg1469Leu	missense	Exon 28 of 32	ENSP00000576013.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000812 AC: 2 AN: 246348 AF XY: 0.00000752

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000893

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000755 AC: 11 AN: 1456430 Hom.: 0 Cov.: 29 AF XY: 0.00000552 AC XY: 4 AN XY: 724304

African (AFR) AF: 0.00 AC: 0 AN: 33178

American (AMR) AF: 0.00 AC: 0 AN: 43928

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26024

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39452

South Asian (SAS) AF: 0.00 AC: 0 AN: 84970

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53006

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5746

European-Non Finnish (NFE) AF: 0.00000631 AC: 7 AN: 1109984

Other (OTH) AF: 0.0000166 AC: 1 AN: 60142

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	17
DANN	Benign	0.46
DEOGEN2	Benign	0.070	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.4	N
PhyloP100		3.0
PrimateAI	Benign	0.33	T
PROVEAN	Benign	4.1	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.24
MutPred		0.60		Gain of glycosylation at Y1491 (P = 0.002)
MVP		0.20
MPC		0.028
ClinPred		0.13	T
GERP RS		3.0
Varity_R		0.040
gMVP		0.26
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs199670262; hg19: chr4-36085023;