6-57196547-A-T

Variant names:

• chr6-57196547-A-T
• rs45479896
• NM_016277.5:c.301T>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016277.5(RAB23):​c.301T>A​(p.Ser101Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S101A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAB23 NM_016277.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.20
• Publications: 0 publications found

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]

RAB23 Gene-Disease associations (from GenCC):

• RAB23-related Carpenter syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• Carpenter syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14583915).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB23	NM_016277.5	c.301T>A	p.Ser101Thr	missense_variant	Exon 4 of 7	ENST00000468148.6	NP_057361.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB23	ENST00000468148.6	c.301T>A	p.Ser101Thr	missense_variant	Exon 4 of 7	1	NM_016277.5	ENSP00000417610.1
RAB23	ENST00000317483.4	c.301T>A	p.Ser101Thr	missense_variant	Exon 4 of 7	1		ENSP00000320413.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	16
DANN	Benign	0.92
DEOGEN2	Benign	0.16	T;T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.87	D;.
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.65	N;N
PhyloP100		1.2
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.69	N;N
REVEL	Benign	0.14
Sift	Benign	0.39	T;T
Sift4G	Benign	0.36	T;T
Polyphen		0.0010	B;B
Vest4		0.24
MutPred		0.29		Loss of disorder (P = 0.0581);Loss of disorder (P = 0.0581);
MVP		0.72
MPC		0.16
ClinPred		0.12	T
GERP RS		0.76
Varity_R		0.051
gMVP		0.26
Mutation Taster		=91/9	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: rs45479896; hg19: chr6-57061345;