Genetic Variant RANGAP1:p.Val563Met (chr22-41249337-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_002883.4(RANGAP1):c.1687G>A(p.Val563Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000181 in 1,602,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V563L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

RANGAP1
NM_002883.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.65

Publications

1 publications found

Variant links:

Genes affected

RANGAP1 (HGNC:9854): (Ran GTPase activating protein 1) This gene encodes a protein that associates with the nuclear pore complex and participates in the regulation of nuclear transport. The encoded protein interacts with Ras-related nuclear protein 1 (RAN) and regulates guanosine triphosphate (GTP)-binding and exchange. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

RANGAP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.054968446).

BP6

Variant 22-41249337-C-T is Benign according to our data. Variant chr22-41249337-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2491150.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAdExome4 at 25 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002883.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RANGAP1	NM_002883.4	MANE Select	c.1687G>A	p.Val563Met	missense	Exon 15 of 16	NP_002874.1	P46060
RANGAP1	NM_001278651.2		c.1687G>A	p.Val563Met	missense	Exon 16 of 17	NP_001265580.1	P46060
RANGAP1	NM_001317930.2		c.1687G>A	p.Val563Met	missense	Exon 15 of 16	NP_001304859.1	P46060

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RANGAP1	ENST00000356244.8	TSL:1 MANE Select	c.1687G>A	p.Val563Met	missense	Exon 15 of 16	ENSP00000348577.3	P46060
RANGAP1	ENST00000405486.5	TSL:1	c.1687G>A	p.Val563Met	missense	Exon 16 of 17	ENSP00000385866.1	P46060
RANGAP1	ENST00000455915.6	TSL:1	c.1687G>A	p.Val563Met	missense	Exon 14 of 15	ENSP00000401470.2	P46060

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152270

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000415

AC:

AN:

240874

AF XY:

0.0000538

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000297

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000171

GnomAD4 exome

AF:

0.0000172

AC:

AN:

1449618

Hom.:

Cov.:

AF XY:

0.0000181

AC XY:

AN XY:

719896

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33322

American (AMR)

AF:

0.0000457

AC:

AN:

43802

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25084

East Asian (EAS)

AF:

0.000253

AC:

AN:

39580

South Asian (SAS)

AF:

0.0000474

AC:

AN:

84416

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52646

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.00000543

AC:

AN:

1105194

Other (OTH)

AF:

0.0000334

AC:

AN:

59872

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000262

AC:

AN:

152388

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74520

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41602

American (AMR)

AF:

0.000131

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

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:

0.00

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000330

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

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

0.16

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.17

(source)

DANN

Benign

0.57

DEOGEN2

Benign

0.15

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.34

M_CAP

Benign

0.013

MetaRNN

Benign

0.055

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.18

PhyloP100

-1.7

PrimateAI

Benign

0.33

PROVEAN

Benign

0.17

REVEL

Benign

0.13

Sift

Benign

0.39

Sift4G

Benign

0.55

Polyphen

0.069

Vest4

0.17

MutPred

0.72

Loss of ubiquitination at K565 (P = 0.0709)

MVP

0.15

MPC

0.23

ClinPred

0.024

GERP RS

-4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.19

gMVP

0.20

Mutation Taster

=89/11

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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