NM_171998.4:c.428C>G

Variant names:

• chrX-155261017-G-C
• rs864309528
• NM_171998.4:c.428C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_171998.4(RAB39B):​c.428C>G​(p.Ala143Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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: 22)
• Consequence: RAB39B NM_171998.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.04
• Publications: 2 publications found

Genes affected

RAB39B (HGNC:16499): (RAB39B, member RAS oncogene family) This gene encodes a member of the Rab family of proteins. Rab proteins are small GTPases that are involved in vesicular trafficking. Mutations in this gene are associated with X-linked cognitive disability. [provided by RefSeq, Aug 2013]

RAB39B Gene-Disease associations (from GenCC):

• early-onset parkinsonism-intellectual disability syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• intellectual disability, X-linked 72

  Inheritance: XL Classification: DEFINITIVE, MODERATE Submitted by: Ambry Genetics, G2P
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 3 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.9438 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to early-onset parkinsonism-intellectual disability syndrome, intellectual disability, X-linked 72, non-syndromic X-linked intellectual disability.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2260947).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_171998.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB39B	NM_171998.4	MANE Select	c.428C>G	p.Ala143Gly	missense	Exon 2 of 2	NP_741995.1	Q96DA2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB39B	ENST00000369454.4	TSL:1 MANE Select	c.428C>G	p.Ala143Gly	missense	Exon 2 of 2	ENSP00000358466.3	Q96DA2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Parkinson disease, X-linked dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	0.39	N
PhyloP100		4.0
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.24
Sift	Benign	0.15	T
Sift4G	Benign	0.37	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.34		Gain of catalytic residue at A142 (P = 0.0626)
MVP		0.74
MPC		1.2
ClinPred		0.64	D
GERP RS		5.2
Varity_R		0.68
gMVP		0.42
Mutation Taster		=58/42	polymorphism

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

Other links and lift over

dbSNP: rs864309528; hg19: chrX-154490302;