Variant 9-123020426-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_012197.4(RABGAP1):c.1761C>G(p.His587Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000468 in 1,603,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

RABGAP1
NM_012197.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.89

Variant links:

Genes affected

RABGAP1 (HGNC:17155): (RAB GTPase activating protein 1) Enables GTPase activator activity and small GTPase binding activity. Involved in regulation of GTPase activity. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

RABGAP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2

Missense variant where missense usually causes diseases, RABGAP1

BP4

Computational evidence support a benign effect (MetaRNN=0.07662925).

BS2

High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RABGAP1	NM_012197.4 linkuse as main transcript	c.1761C>G	p.His587Gln	missense_variant	13/26	ENST00000373647.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RABGAP1	ENST00000373647.9 linkuse as main transcript	c.1761C>G	p.His587Gln	missense_variant	13/26	1	NM_012197.4	P1	Q9Y3P9-1
RABGAP1	ENST00000456584.5 linkuse as main transcript	c.1557C>G	p.His519Gln	missense_variant, NMD_transcript_variant	14/28	2			Q9Y3P9-2

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152144

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:

0.000162

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000446

AC:

AN:

246384

Hom.:

AF XY:

0.0000451

AC XY:

AN XY:

133180

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000974

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000434

AC:

AN:

1451636

Hom.:

Cov.:

AF XY:

0.0000457

AC XY:

AN XY:

721570

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000551

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74462

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:

0.000162

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000123

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.0000576

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

Jun 30, 2022

The c.1761C>G (p.H587Q) alteration is located in exon 13 (coding exon 12) of the RABGAP1 gene. This alteration results from a C to G substitution at nucleotide position 1761, causing the histidine (H) at amino acid position 587 to be replaced by a glutamine (Q). 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

0.086

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.052

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.35

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.012

MetaRNN

Benign

0.077

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.26

MutationTaster

Benign

0.99

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

0.050

REVEL

Benign

0.082

Sift

Benign

0.18

Sift4G

Benign

0.22

Polyphen

0.0010

Vest4

0.23

MutPred

0.39

Loss of ubiquitination at K591 (P = 0.0724);

MVP

0.15

MPC

0.62

ClinPred

0.056

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.23

gMVP

0.53

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