11-72702914-G-C

Variant names:

• chr11-72702914-G-C
• rs778865505
• NM_001040118.3:c.2158C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001040118.3(ARAP1):​c.2158C>G​(p.Arg720Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000285 in 1,402,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R720Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: ARAP1 NM_001040118.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.70
• Publications: 0 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-AS2 (HGNC:39994): (ARAP1 antisense RNA 2)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09958017).

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.2158C>G	p.Arg720Gly	missense	Exon 15 of 35	NP_001035207.1	Q96P48-6
	ARAP1	NM_015242.5		c.1423C>G	p.Arg475Gly	missense	Exon 13 of 33	NP_056057.2	Q96P48-4
	ARAP1	NM_001369489.1		c.1423C>G	p.Arg475Gly	missense	Exon 13 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.2158C>G	p.Arg720Gly	missense	Exon 15 of 35	ENSP00000377233.3	Q96P48-6
	ARAP1	ENST00000393605.7	TSL:1	c.1438C>G	p.Arg480Gly	missense	Exon 10 of 30	ENSP00000377230.3	Q96P48-1
	ARAP1	ENST00000334211.12	TSL:1	c.1423C>G	p.Arg475Gly	missense	Exon 13 of 33	ENSP00000335506.8	Q96P48-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 160664 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000285 AC: 4 AN: 1402204 Hom.: 0 Cov.: 31 AF XY: 0.00000289 AC XY: 2 AN XY: 691970

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31854

American (AMR) AF: 0.0000555 AC: 2 AN: 36046

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25194

East Asian (EAS) AF: 0.00 AC: 0 AN: 36096

South Asian (SAS) AF: 0.00 AC: 0 AN: 79532

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49140

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5658

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1080566

Other (OTH) AF: 0.00 AC: 0 AN: 58118

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000100134), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	0.11
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.14	N
PhyloP100		1.7
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.072
Sift	Benign	0.21	T
Sift4G	Uncertain	0.027	D
Polyphen		0.12	B
Vest4		0.28
MutPred		0.46		Loss of stability (P = 0.0297)
MVP		0.30
MPC		0.41
ClinPred		0.38	T
GERP RS		4.0
PromoterAI		-0.0080	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.25
Mutation Taster		=86/14	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: rs778865505; hg19: chr11-72413959;