Variant 22-41254406-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_002883.4(RANGAP1):c.1162G>A(p.Glu388Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00016 in 1,613,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

RANGAP1
NM_002883.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.18

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 made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3094152).

BS2

High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RANGAP1	NM_002883.4 linkuse as main transcript	c.1162G>A	p.Glu388Lys	missense_variant	11/16	ENST00000356244.8	NP_002874.1	P46060A0A024R1U0Q9BSK3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RANGAP1	ENST00000356244.8 linkuse as main transcript	c.1162G>A	p.Glu388Lys	missense_variant	11/16	1	NM_002883.4	ENSP00000348577.3	P46060
RANGAP1	ENST00000405486.5 linkuse as main transcript	c.1162G>A	p.Glu388Lys	missense_variant	12/17	1		ENSP00000385866.1	P46060
RANGAP1	ENST00000455915.6 linkuse as main transcript	c.1162G>A	p.Glu388Lys	missense_variant	10/15	1		ENSP00000401470.2	P46060
RANGAP1	ENST00000705116.1 linkuse as main transcript	c.1162G>A	p.Glu388Lys	missense_variant	11/16			ENSP00000516069.1	P46060

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000563

AC:

AN:

248760

Hom.:

AF XY:

0.0000594

AC XY:

AN XY:

134692

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000108

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000170

AC:

248

AN:

1461510

Hom.:

Cov.:

AF XY:

0.000150

AC XY:

109

AN XY:

727050

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000211

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.0000658

AC:

AN:

152062

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000254

Hom.:

Bravo

AF:

0.000106

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 11, 2023

The c.1162G>A (p.E388K) alteration is located in exon 11 (coding exon 10) of the RANGAP1 gene. This alteration results from a G to A substitution at nucleotide position 1162, causing the glutamic acid (E) at amino acid position 388 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.078

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.38

T;T;T

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.64

LIST_S2

Uncertain

0.88

.;.;D

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.31

T;T;T

MetaSVM

Uncertain

0.35

MutationAssessor

Benign

1.9

L;L;L

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.1

N;N;N

REVEL

Uncertain

0.36

Sift

Benign

0.12

T;T;T

Sift4G

Benign

0.24

T;T;T

Polyphen

0.021

B;B;B

Vest4

0.44

MVP

0.83

MPC

0.25

ClinPred

0.10

GERP RS

4.3

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

3.2

Varity_R

0.089

gMVP

0.13

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over