Genetic Variant NM_020336.4:c.2324G>T (chr20-38535152-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP5_Moderate

The NM_020336.4(RALGAPB):c.2324G>T(p.Arg775Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

RALGAPB
NM_020336.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.63

Publications

1 publications found

Variant links:

Genes affected

RALGAPB (HGNC:29221): (Ral GTPase activating protein non-catalytic subunit beta) Enables protein heterodimerization activity. Predicted to be involved in activation of GTPase activity. Predicted to act upstream of or within Ral protein signal transduction; regulation of exocyst localization; and regulation of protein localization. [provided by Alliance of Genome Resources, Apr 2022]

RALGAPB Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

RALGAPB links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 20-38535152-G-T is Pathogenic according to our data. Variant chr20-38535152-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 370037.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020336.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RALGAPB	NM_020336.4	MANE Select	c.2324G>T	p.Arg775Leu	missense	Exon 16 of 30	NP_065069.1
RALGAPB	NM_001282917.2		c.2324G>T	p.Arg775Leu	missense	Exon 16 of 30	NP_001269846.1
RALGAPB	NM_001282918.2		c.2312G>T	p.Arg771Leu	missense	Exon 16 of 30	NP_001269847.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RALGAPB	ENST00000262879.11	TSL:1 MANE Select	c.2324G>T	p.Arg775Leu	missense	Exon 16 of 30	ENSP00000262879.6
RALGAPB	ENST00000397040.5	TSL:1	c.2324G>T	p.Arg775Leu	missense	Exon 16 of 30	ENSP00000380233.1
RALGAPB	ENST00000397042.7	TSL:1	c.2312G>T	p.Arg771Leu	missense	Exon 16 of 30	ENSP00000380235.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251422

AF XY:

0.00000736

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Septo-optic dysplasia sequence

Pathogenic:1

Oct 06, 2016

Shaikh Laboratory, University of Colorado

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.19

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.011

MetaRNN

Uncertain

0.52

MetaSVM

Benign

-0.37

MutationAssessor

Benign

1.8

PhyloP100

7.6

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-3.3

REVEL

Uncertain

0.36

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.011

Polyphen

0.99

Vest4

0.75

MutPred

0.34

Loss of MoRF binding (P = 0.0157)

MVP

0.28

MPC

1.3

ClinPred

0.94

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.37

gMVP

0.59

Mutation Taster

=48/52

disease causing (ClinVar)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over