11-82997265-C-T

Variant names:

• chr11-82997265-C-T
• rs376604970
• NM_001286060.2:c.52G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001286060.2(RAB30):​c.52G>A​(p.Ala18Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,728 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A18G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: RAB30 NM_001286060.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

Genes affected

RAB30 (HGNC:9770): (RAB30, member RAS oncogene family) Predicted to enable GTP binding activity and GTPase activity. Involved in Golgi organization. Located in Golgi cisterna; cis-Golgi network; and trans-Golgi network. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000254698 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB30	NM_001286060.2	c.52G>A	p.Ala18Thr	missense_variant	Exon 2 of 5	ENST00000527633.6	NP_001272989.1
RAB30	NM_001286059.2	c.52G>A	p.Ala18Thr	missense_variant	Exon 2 of 5		NP_001272988.1
RAB30	NM_001286061.1	c.52G>A	p.Ala18Thr	missense_variant	Exon 2 of 5		NP_001272990.1
RAB30	NM_014488.5	c.52G>A	p.Ala18Thr	missense_variant	Exon 3 of 6		NP_055303.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB30	ENST00000527633.6	c.52G>A	p.Ala18Thr	missense_variant	Exon 2 of 5	1	NM_001286060.2	ENSP00000435089.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251446 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135898

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460728 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726788

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.52G>A (p.A18T) alteration is located in exon 3 (coding exon 1) of the RAB30 gene. This alteration results from a G to A substitution at nucleotide position 52, causing the alanine (A) at amino acid position 18 to be replaced by a threonine (T). 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	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.53	D;D;.;D;D;T;T;T;T;T;T;D;T;.
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D;.;D;.;.;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.069	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	-0.40	N;N;N;N;N;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.7	.;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.022	.;D;T;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.062	T;T;D;T;T;.;.;D;D;D;D;.;D;.
Polyphen		1.0	D;D;.;D;D;.;.;D;.;.;.;.;.;.
Vest4		0.71
MVP		0.77
MPC		1.8
ClinPred		0.85	D
GERP RS		5.8
Varity_R		0.51
gMVP		0.84

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: rs376604970; hg19: chr11-82708307;