Genetic Variant RANGAP1:p.Val518Met (chr22-41249749-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_002883.4(RANGAP1):c.1552G>A(p.Val518Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,542 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

RANGAP1
NM_002883.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.388

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 -4 ACMG points.

BS2

High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RANGAP1	NM_002883.4 link	c.1552G>A	p.Val518Met	missense_variant	Exon 14 of 16	ENST00000356244.8	NP_002874.1	P46060A0A024R1U0Q9BSK3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RANGAP1	ENST00000356244.8 link	c.1552G>A	p.Val518Met	missense_variant	Exon 14 of 16	1	NM_002883.4	ENSP00000348577.3	P46060
RANGAP1	ENST00000405486.5 link	c.1552G>A	p.Val518Met	missense_variant	Exon 15 of 17	1		ENSP00000385866.1	P46060
RANGAP1	ENST00000455915.6 link	c.1552G>A	p.Val518Met	missense_variant	Exon 13 of 15	1		ENSP00000401470.2	P46060
RANGAP1	ENST00000705116.1 link	c.1552G>A	p.Val518Met	missense_variant	Exon 14 of 16			ENSP00000516069.1	P46060

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251366

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461542

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727112

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1552G>A (p.V518M) alteration is located in exon 14 (coding exon 13) of the RANGAP1 gene. This alteration results from a G to A substitution at nucleotide position 1552, causing the valine (V) at amino acid position 518 to be replaced by a methionine (M). 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

0.27

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

T;T;T

Eigen

Benign

0.071

Eigen_PC

Benign

-0.070

FATHMM_MKL

Benign

0.69

LIST_S2

Uncertain

0.91

.;.;D

M_CAP

Benign

0.039

MetaRNN

Uncertain

0.58

D;D;D

MetaSVM

Benign

-0.76

MutationAssessor

Uncertain

2.4

M;M;M

PrimateAI

Benign

0.27

PROVEAN

Benign

-2.3

N;N;N

REVEL

Benign

0.18

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

0.99

D;D;D

Vest4

0.29

MutPred

0.74

Gain of disorder (P = 0.2024);Gain of disorder (P = 0.2024);Gain of disorder (P = 0.2024);

MVP

0.61

MPC

0.80

ClinPred

0.72

GERP RS

-0.10

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.43

gMVP

0.38

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