chr11-72693802-C-A

Variant names:

• chr11-72693802-C-A
• rs147016656
• NM_001040118.3:c.3698G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001040118.3(ARAP1):​c.3698G>T​(p.Arg1233Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,445,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1233H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ARAP1 NM_001040118.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.40
• 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-AS1 (HGNC:39993): (ARAP1 antisense RNA 1)

ENSG00000286555 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.856

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.3698G>T	p.Arg1233Leu	missense	Exon 28 of 35	NP_001035207.1	Q96P48-6
	ARAP1	NM_015242.5		c.2963G>T	p.Arg988Leu	missense	Exon 26 of 33	NP_056057.2	Q96P48-4
	ARAP1	NM_001369489.1		c.2963G>T	p.Arg988Leu	missense	Exon 26 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.3698G>T	p.Arg1233Leu	missense	Exon 28 of 35	ENSP00000377233.3	Q96P48-6
	ARAP1	ENST00000393605.7	TSL:1	c.2978G>T	p.Arg993Leu	missense	Exon 23 of 30	ENSP00000377230.3	Q96P48-1
	ARAP1	ENST00000334211.12	TSL:1	c.2963G>T	p.Arg988Leu	missense	Exon 26 of 33	ENSP00000335506.8	Q96P48-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000457 AC: 1 AN: 218792 AF XY: 0.00000845

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: 6.92e-7 AC: 1 AN: 1445136 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 717760

⚠️ 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: 33172

American (AMR) AF: 0.00 AC: 0 AN: 42462

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25766

East Asian (EAS) AF: 0.00 AC: 0 AN: 38850

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 83864

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50900

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104682

Other (OTH) AF: 0.00 AC: 0 AN: 59712

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000826 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.4
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MVP		0.79
MPC		1.2
ClinPred		0.99	D
GERP RS		5.8
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.72
gMVP		0.96
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs147016656; hg19: chr11-72404847;