11-88149682-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_022337.3(RAB38):c.476C>T(p.Ser159Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RAB38 NM_022337.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.48

Genes affected

RAB38 (HGNC:9776): (RAB38, member RAS oncogene family) Enables several functions, including AP-1 adaptor complex binding activity; AP-3 adaptor complex binding activity; and BLOC-2 complex binding activity. Involved in several processes, including endosome to melanosome transport; melanosome assembly; and phagosome acidification. Located in several cellular components, including cytoplasmic vesicle; lysosome; and mitochondria-associated endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAB38	NM_022337.3	c.476C>T	p.Ser159Leu	missense_variant	2/3	ENST00000243662.11
RAB38	XM_017017455.3	c.476C>T	p.Ser159Leu	missense_variant	2/4
RAB38	XM_017017456.3	c.476C>T	p.Ser159Leu	missense_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAB38	ENST00000243662.11	c.476C>T	p.Ser159Leu	missense_variant	2/3	1	NM_022337.3	P1
RAB38	ENST00000526372.1	c.473C>T	p.Ser158Leu	missense_variant	2/3	3
RAB38	ENST00000531138.1	c.251+25501C>T		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455632 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 722788

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: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 05, 2023

The c.476C>T (p.S159L) alteration is located in exon 2 (coding exon 2) of the RAB38 gene. This alteration results from a C to T substitution at nucleotide position 476, causing the serine (S) at amino acid position 159 to be replaced by a leucine (L). 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	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.96		Loss of disorder (P = 0.037);
MVP		0.98
MPC		0.41
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.99
gMVP		0.91

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-87882850;