11-66276155-C-T

Variant names:

• chr11-66276155-C-T
• rs1393503361
• NM_030981.3:c.523C>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_030981.3(RAB1B):​c.523C>T​(p.Pro175Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,460,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: RAB1B NM_030981.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.13

Genes affected

RAB1B (HGNC:18370): (RAB1B, member RAS oncogene family) Members of the RAB protein family, such as RAB1B, are low molecular mass monomeric GTPases localized on the cytoplasmic surfaces of distinct membrane-bound organelles. RAB1B functions in the early secretory pathway and is essential for vesicle transport between the endoplasmic reticulum (ER) and Golgi (Chen et al., 1997 [PubMed 9030196]; Alvarez et al., 2003 [PubMed 12802079]).[supplied by OMIM, Jan 2009]

ENSG00000245156 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.103058904).
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB1B	NM_030981.3	c.523C>T	p.Pro175Ser	missense_variant	Exon 6 of 6	ENST00000311481.11	NP_112243.1
LOC107984340	XR_001748274.1	n.31+2340G>A		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB1B	ENST00000311481.11	c.523C>T	p.Pro175Ser	missense_variant	Exon 6 of 6	1	NM_030981.3	ENSP00000310226.6
RAB1B	ENST00000527397.1	c.427C>T	p.Pro143Ser	missense_variant	Exon 5 of 5	3		ENSP00000435195.1
ENSG00000245156	ENST00000501708.1	n.31+2340G>A		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1460404 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 726506

Gnomad4 AFR exome AF: 0.0000599

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: 0.00000630

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.523C>T (p.P175S) alteration is located in exon 6 (coding exon 6) of the RAB1B gene. This alteration results from a C to T substitution at nucleotide position 523, causing the proline (P) at amino acid position 175 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	0.0048	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Benign	0.85
DEOGEN2	Benign	0.020	T;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-0.84	T
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	0.50	N;N
REVEL	Uncertain	0.32
Sift	Benign	0.94	T;T
Sift4G	Benign	0.68	T;T
Polyphen		0.0010	B;.
Vest4		0.14
MutPred		0.37		Gain of phosphorylation at P175 (P = 0.0097);.;
MVP		0.46
MPC		0.13
ClinPred		0.24	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.63

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: rs1393503361; hg19: chr11-66043626;