rs45442500

Positions:

• chr6-57210262-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_016277.5(RAB23):​c.119A>G​(p.Lys40Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: RAB23 NM_016277.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.01

Genes affected

RAB23 (HGNC:14263): (RAB23, member RAS oncogene family) This gene encodes a small GTPase of the Ras superfamily. Rab proteins are involved in the regulation of diverse cellular functions associated with intracellular membrane trafficking, including autophagy and immune response to bacterial infection. The encoded protein may play a role in central nervous system development by antagonizing sonic hedgehog signaling. Disruption of this gene has been implicated in Carpenter syndrome as well as cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.809

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAB23	NM_016277.5	c.119A>G	p.Lys40Arg	missense_variant	2/7	ENST00000468148.6	NP_057361.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAB23	ENST00000468148.6	c.119A>G	p.Lys40Arg	missense_variant	2/7	1	NM_016277.5	ENSP00000417610.1
RAB23	ENST00000317483.4	c.119A>G	p.Lys40Arg	missense_variant	2/7	1		ENSP00000320413.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461766 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727176

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: 0.0000135

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	T;T
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;.
M_CAP	Benign	0.079	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Uncertain	-0.039	T
MutationAssessor	Benign	1.3	L;L
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.39
Sift	Benign	0.034	D;D
Sift4G	Uncertain	0.022	D;D
Polyphen		1.0	D;D
Vest4		0.72
MutPred		0.17		Loss of ubiquitination at K40 (P = 0.0326);Loss of ubiquitination at K40 (P = 0.0326);
MVP		0.83
MPC		0.65
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.85
gMVP		0.59

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

Other links and lift over

dbSNP: rs45442500; hg19: chr6-57075060;