chr19-8399886-G-A

Variant names:

• chr19-8399886-G-A
• rs1555690779
• NM_004218.4:c.64G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_004218.4(RAB11B):​c.64G>A​(p.Val22Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. V22V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: RAB11B NM_004218.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 10.0
• Publications: 1 publications found

Genes affected

RAB11B (HGNC:9761): (RAB11B, member RAS oncogene family) The Ras superfamily of small GTP-binding proteins, which includes the Ras (see MIM 190020), Ral (see MIM 179550), Rho (see MIM 165390), Rap (see MIM 179520), and Rab (see MIM 179508) families, is involved in controlling a diverse set of essential cellular functions. The Rab family, including RAB11B, appears to play a critical role in regulating exocytotic and endocytotic pathways (summary by Zhu et al., 1994 [PubMed 7811277]).[supplied by OMIM, Nov 2010]

RAB11B Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95
• PP5: Variant 19-8399886-G-A is Pathogenic according to our data. Variant chr19-8399886-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 453254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004218.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB11B	NM_004218.4	MANE Select	c.64G>A	p.Val22Met	missense	Exon 2 of 5	NP_004209.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB11B	ENST00000328024.11	TSL:1 MANE Select	c.64G>A	p.Val22Met	missense	Exon 2 of 5	ENSP00000333547.5
	RAB11B	ENST00000600719.5	TSL:4	c.-294G>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 4	ENSP00000473042.1
	RAB11B	ENST00000594216.1	TSL:2	c.64G>A	p.Val22Met	missense	Exon 2 of 4	ENSP00000471148.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter (4)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	4.5	H
PhyloP100		10
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.86		Loss of catalytic residue at V22 (P = 0.0054)
MVP		0.90
MPC		2.4
ClinPred		1.0	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.82
gMVP		0.92
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555690779; hg19: chr19-8464770; COSMIC: COSV105897607;