NM_001040118.3:c.4222G>A

Variant names:

• chr11-72686155-C-T
• rs2291288
• NM_001040118.3:c.4222G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001040118.3(ARAP1):​c.4222G>A​(p.Val1408Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00439 in 1,613,864 control chromosomes in the GnomAD database, including 277 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (32 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (245 hom.)
• Consequence: ARAP1 NM_001040118.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.75
• Publications: 3 publications found

Genes affected

ARAP1 (HGNC:16925): (ArfGAP with RhoGAP domain, ankyrin repeat and PH domain 1) The protein encoded by this gene contains SAM, ARF-GAP, RHO-GAP, ankyrin repeat, RAS-associating, and pleckstrin homology (PH) domains. In vitro, this protein displays RHO-GAP and phosphatidylinositol (3,4,5) trisphosphate (PIP3)-dependent ARF-GAP activity. The encoded protein associates with the Golgi, and the ARF-GAP activity mediates changes in the Golgi and the formation of filopodia. It is thought to regulate the cell-specific trafficking of a receptor protein involved in apoptosis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2008]

ARAP1-AS1 (HGNC:39993): (ARAP1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017605126).
• BP6: Variant 11-72686155-C-T is Benign according to our data. Variant chr11-72686155-C-T is described in ClinVar as Benign. ClinVar VariationId is 770219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0754 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040118.3. 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
	ARAP1	NM_001040118.3	MANE Select	c.4222G>A	p.Val1408Met	missense	Exon 34 of 35	NP_001035207.1	Q96P48-6
	ARAP1	NM_015242.5		c.3487G>A	p.Val1163Met	missense	Exon 32 of 33	NP_056057.2	Q96P48-4
	ARAP1	NM_001369489.1		c.3454G>A	p.Val1152Met	missense	Exon 31 of 32	NP_001356418.1	E7EU13

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARAP1	ENST00000393609.8	TSL:2 MANE Select	c.4222G>A	p.Val1408Met	missense	Exon 34 of 35	ENSP00000377233.3	Q96P48-6
	ARAP1	ENST00000393605.7	TSL:1	c.3502G>A	p.Val1168Met	missense	Exon 29 of 30	ENSP00000377230.3	Q96P48-1
	ARAP1	ENST00000334211.12	TSL:1	c.3487G>A	p.Val1163Met	missense	Exon 32 of 33	ENSP00000335506.8	Q96P48-4

Frequencies

GnomAD3 genomes AF: 0.00771 AC: 1173 AN: 152164 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0409

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0817

Gnomad SAS AF: 0.00601

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.0120 AC: 3007 AN: 250486 AF XY: 0.0103

Gnomad AFR exome AF: 0.000930

Gnomad AMR exome AF: 0.0365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0875

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.00850

GnomAD4 exome AF: 0.00404 AC: 5910 AN: 1461582 Hom.: 245 Cov.: 33 AF XY: 0.00376 AC XY: 2732 AN XY: 727106

African (AFR) AF: 0.000568 AC: 19 AN: 33478

American (AMR) AF: 0.0377 AC: 1688 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0853 AC: 3387 AN: 39698

South Asian (SAS) AF: 0.00214 AC: 185 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53208

Middle Eastern (MID) AF: 0.000698 AC: 4 AN: 5732

European-Non Finnish (NFE) AF: 0.000121 AC: 134 AN: 1111978

Other (OTH) AF: 0.00816 AC: 493 AN: 60382

GnomAD4 genome AF: 0.00770 AC: 1172 AN: 152282 Hom.: 32 Cov.: 32 AF XY: 0.00882 AC XY: 657 AN XY: 74460

African (AFR) AF: 0.00140 AC: 58 AN: 41564

American (AMR) AF: 0.0408 AC: 623 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0819 AC: 424 AN: 5180

South Asian (SAS) AF: 0.00601 AC: 29 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68024

Other (OTH) AF: 0.0109 AC: 23 AN: 2114

Alfa AF: 0.00157 Hom.: 2

Bravo AF: 0.0102

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00946 AC: 1148

Asia WGS AF: 0.0410 AC: 143 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.051
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		2.7
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.081
Sift	Benign	0.098	T
Sift4G	Benign	0.46	T
Polyphen		0.16	B
Vest4		0.20
MPC		0.34
ClinPred		0.015	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.074
gMVP		0.38
Mutation Taster		=99/1	polymorphism (auto)

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: rs2291288; hg19: chr11-72397200; COSMIC: COSV61990778; COSMIC: COSV61990778;