Variant 22-41254460-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002883.4(RANGAP1):c.1108G>A(p.Glu370Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,454,474 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RANGAP1
NM_002883.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.28

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21330911).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RANGAP1	NM_002883.4 linkuse as main transcript	c.1108G>A	p.Glu370Lys	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.1108G>A	p.Glu370Lys	missense_variant	11/16	1	NM_002883.4	ENSP00000348577.3	P46060
RANGAP1	ENST00000405486.5 linkuse as main transcript	c.1108G>A	p.Glu370Lys	missense_variant	12/17	1		ENSP00000385866.1	P46060
RANGAP1	ENST00000455915.6 linkuse as main transcript	c.1108G>A	p.Glu370Lys	missense_variant	10/15	1		ENSP00000401470.2	P46060
RANGAP1	ENST00000705116.1 linkuse as main transcript	c.1108G>A	p.Glu370Lys	missense_variant	11/16			ENSP00000516069.1	P46060

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000828

AC:

AN:

241526

Hom.:

AF XY:

0.00000766

AC XY:

AN XY:

130630

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS 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:

0.00000138

AC:

AN:

1454474

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723360

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Oct 05, 2023

The c.1108G>A (p.E370K) 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 1108, causing the glutamic acid (E) at amino acid position 370 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

0.13

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.46

T;T;T

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.85

.;.;D

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.21

T;T;T

MetaSVM

Uncertain

0.12

MutationAssessor

Uncertain

2.1

M;M;M

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.2

N;N;N

REVEL

Benign

0.23

Sift

Benign

0.036

D;D;D

Sift4G

Benign

0.11

T;T;T

Polyphen

0.13

B;B;B

Vest4

0.30

MutPred

0.23

Gain of glycosylation at E370 (P = 0.0151);Gain of glycosylation at E370 (P = 0.0151);Gain of glycosylation at E370 (P = 0.0151);

MVP

0.80

MPC

0.26

ClinPred

0.17

GERP RS

4.2

Varity_R

0.076

gMVP

0.076

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