chr5-141679591-C-G

Position:

• chr5-141679591-C-G

Variant summary

Our verdict is Benign. Variant got -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. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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 Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARAP3	NM_022481.6	c.652G>C	p.Asp218His	missense_variant	4/33	ENST00000239440.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARAP3	ENST00000239440.9	c.652G>C	p.Asp218His	missense_variant	4/33	1	NM_022481.6	P1
ARAP3	ENST00000504448.1	c.652G>C	p.Asp218His	missense_variant	3/9	1
ARAP3	ENST00000508305.5	c.418G>C	p.Asp140His	missense_variant	4/32	2
ARAP3	ENST00000626478.2	c.418G>C	p.Asp140His	missense_variant	3/31	5

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

GnomAD3 exomes AF: 0.112 AC: 28199 AN: 251434 Hom.: 1770 AF XY: 0.116 AC XY: 15731 AN XY: 135898

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 SAS exome AF: 0.158

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

Gnomad4 AFR exome AF: 0.0314

Gnomad4 AMR exome AF: 0.100

Gnomad4 ASJ exome AF: 0.114

Gnomad4 EAS exome AF: 0.104

Gnomad4 SAS exome AF: 0.158

Gnomad4 FIN exome AF: 0.116

Gnomad4 NFE exome AF: 0.123

Gnomad4 OTH exome AF: 0.112

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

Gnomad4 AFR AF: 0.0333

Gnomad4 AMR AF: 0.0981

Gnomad4 ASJ AF: 0.106

Gnomad4 EAS AF: 0.0758

Gnomad4 SAS AF: 0.154

Gnomad4 FIN AF: 0.114

Gnomad4 NFE AF: 0.126

Gnomad4 OTH AF: 0.105

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 v4.3

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;T;T;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.57	.;T;T;T
MetaRNN	Benign	0.0016	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	.;L;.;.
MutationTaster	Benign	0.97	P;P;P
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.0	N;N;.;N
REVEL	Benign	0.038
Sift	Uncertain	0.0020	D;D;.;D
Sift4G	Uncertain	0.046	D;T;D;.
Polyphen		0.75	P;B;P;.
Vest4		0.26
MPC		0.70
ClinPred		0.011	T
GERP RS		2.2
Varity_R		0.10
gMVP		0.32

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

Publications

LitVar

Other links and lift over

dbSNP: rs1031904; hg19: chr5-141059158; COSMIC: COSV53352682;