Genetic Variant NM_001040118.3:c.2096C>T (chr11-72702976-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001040118.3(ARAP1):c.2096C>T(p.Thr699Met) variant causes a missense change. The variant allele was found at a frequency of 0.000564 in 1,568,130 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00058 ( 1 hom. )

Consequence

ARAP1
NM_001040118.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.57

Publications

3 publications found

Variant links:

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 links:

ARAP1-AS2 (HGNC:39994): (ARAP1 antisense RNA 2)

ARAP1-AS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020041257).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARAP1	NM_001040118.3	MANE Select	c.2096C>T	p.Thr699Met	missense	Exon 15 of 35	NP_001035207.1	Q96P48-6
ARAP1	NM_015242.5		c.1361C>T	p.Thr454Met	missense	Exon 13 of 33	NP_056057.2	Q96P48-4
ARAP1	NM_001369489.1		c.1361C>T	p.Thr454Met	missense	Exon 13 of 32	NP_001356418.1	E7EU13

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARAP1	ENST00000393609.8	TSL:2 MANE Select	c.2096C>T	p.Thr699Met	missense	Exon 15 of 35	ENSP00000377233.3	Q96P48-6
ARAP1	ENST00000393605.7	TSL:1	c.1376C>T	p.Thr459Met	missense	Exon 10 of 30	ENSP00000377230.3	Q96P48-1
ARAP1	ENST00000334211.12	TSL:1	c.1361C>T	p.Thr454Met	missense	Exon 13 of 33	ENSP00000335506.8	Q96P48-4

Frequencies

GnomAD3 genomes

AF:

0.000394

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000647

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000564

AC:

100

AN:

177402

AF XY:

0.000663

show subpopulations

Gnomad AFR exome

AF:

0.000100

Gnomad AMR exome

AF:

0.000191

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000250

Gnomad NFE exome

AF:

0.000781

Gnomad OTH exome

AF:

0.000209

GnomAD4 exome

AF:

0.000582

AC:

824

AN:

1415872

Hom.:

Cov.:

AF XY:

0.000644

AC XY:

451

AN XY:

700068

show subpopulations

African (AFR)

AF:

0.0000926

AC:

AN:

32388

American (AMR)

AF:

0.000162

AC:

AN:

37108

Ashkenazi Jewish (ASJ)

AF:

0.0000394

AC:

AN:

25364

East Asian (EAS)

AF:

0.00

AC:

AN:

37254

South Asian (SAS)

AF:

0.00141

AC:

113

AN:

80388

European-Finnish (FIN)

AF:

0.000263

AC:

AN:

49426

Middle Eastern (MID)

AF:

0.000350

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

0.000610

AC:

665

AN:

1089514

Other (OTH)

AF:

0.000358

AC:

AN:

58722

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

105

157

210

262

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000401

AC:

AN:

152258

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0000963

AC:

AN:

41546

American (AMR)

AF:

0.000196

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00145

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000647

AC:

AN:

68008

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000560

Hom.:

Bravo

AF:

0.000348

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000704

AC:

ExAC

AF:

0.000509

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.37

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.51

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.017

MetaRNN

Benign

0.020

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

PhyloP100

4.6

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-3.8

REVEL

Benign

0.17

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.53

MVP

0.30

MPC

0.78

ClinPred

0.14

GERP RS

4.0

PromoterAI

-0.0038

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.38

gMVP

0.58

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over