5-141679591-C-G

Variant names:

• chr5-141679591-C-G
• rs1031904
• NM_022481.6:c.652G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022481.6(ARAP3):​c.652G>C​(p.Asp218His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 1,613,940 control chromosomes in the GnomAD database, including 11,938 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.095 (812 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11126 hom.)
• Consequence: ARAP3 NM_022481.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.599
• Publications: 21 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015562177).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.145 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022481.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARAP3	NM_022481.6	MANE Select	c.652G>C	p.Asp218His	missense	Exon 4 of 33	NP_071926.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARAP3	ENST00000239440.9	TSL:1 MANE Select	c.652G>C	p.Asp218His	missense	Exon 4 of 33	ENSP00000239440.4
	ARAP3	ENST00000504448.1	TSL:1	c.652G>C	p.Asp218His	missense	Exon 3 of 9	ENSP00000421148.1
	ARAP3	ENST00000955414.1		c.652G>C	p.Asp218His	missense	Exon 4 of 33	ENSP00000625473.1

Frequencies

GnomAD3 genomes AF: 0.0955 AC: 14520 AN: 152060 Hom.: 811 Cov.: 32

Gnomad AFR AF: 0.0334

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.0983

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.0762

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.102

GnomAD2 exomes AF: 0.112 AC: 28199 AN: 251434 AF XY: 0.116

Gnomad AFR exome AF: 0.0340

Gnomad AMR exome AF: 0.0957

Gnomad ASJ exome AF: 0.113

Gnomad EAS exome AF: 0.0570

Gnomad FIN exome AF: 0.118

Gnomad NFE exome AF: 0.124

Gnomad OTH exome AF: 0.116

GnomAD4 exome AF: 0.121 AC: 176396 AN: 1461762 Hom.: 11126 Cov.: 32 AF XY: 0.122 AC XY: 88796 AN XY: 727192

African (AFR) AF: 0.0314 AC: 1051 AN: 33480

American (AMR) AF: 0.100 AC: 4474 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 2967 AN: 26132

East Asian (EAS) AF: 0.104 AC: 4142 AN: 39700

South Asian (SAS) AF: 0.158 AC: 13653 AN: 86244

European-Finnish (FIN) AF: 0.116 AC: 6193 AN: 53412

Middle Eastern (MID) AF: 0.0889 AC: 513 AN: 5768

European-Non Finnish (NFE) AF: 0.123 AC: 136636 AN: 1111914

Other (OTH) AF: 0.112 AC: 6767 AN: 60390

GnomAD4 genome AF: 0.0954 AC: 14524 AN: 152178 Hom.: 812 Cov.: 32 AF XY: 0.0969 AC XY: 7212 AN XY: 74392

African (AFR) AF: 0.0333 AC: 1385 AN: 41538

American (AMR) AF: 0.0981 AC: 1500 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 367 AN: 3470

East Asian (EAS) AF: 0.0758 AC: 391 AN: 5160

South Asian (SAS) AF: 0.154 AC: 745 AN: 4824

European-Finnish (FIN) AF: 0.114 AC: 1203 AN: 10588

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.126 AC: 8588 AN: 67998

Other (OTH) AF: 0.105 AC: 222 AN: 2108

Alfa AF: 0.0671 Hom.: 104

Bravo AF: 0.0880

TwinsUK AF: 0.128 AC: 474

ALSPAC AF: 0.126 AC: 485

ESP6500AA AF: 0.0365 AC: 161

ESP6500EA AF: 0.120 AC: 1035

ExAC AF: 0.113 AC: 13694

Asia WGS AF: 0.115 AC: 400 AN: 3478

EpiCase AF: 0.123

EpiControl AF: 0.122

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.60
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.038
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.046	D
Polyphen		0.75	P
Vest4		0.26
MPC		0.70
ClinPred		0.011	T
GERP RS		2.2
Varity_R		0.10
gMVP		0.32
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1031904; hg19: chr5-141059158; COSMIC: COSV53352682;