11-88149814-G-A

Variant names:

• chr11-88149814-G-A
• rs917318545
• NM_022337.3:c.344C>T

Variant summary

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

The NM_022337.3(RAB38):​c.344C>T​(p.Pro115Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P115R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RAB38 NM_022337.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.48
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022337.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB38	NM_022337.3	MANE Select	c.344C>T	p.Pro115Leu	missense	Exon 2 of 3	NP_071732.1	P57729

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB38	ENST00000243662.11	TSL:1 MANE Select	c.344C>T	p.Pro115Leu	missense	Exon 2 of 3	ENSP00000243662.5	P57729
	RAB38	ENST00000916357.1		c.344C>T	p.Pro115Leu	missense	Exon 2 of 4	ENSP00000586416.1
	RAB38	ENST00000526372.1	TSL:3	c.338C>T	p.Pro113Leu	missense	Exon 2 of 3	ENSP00000433317.1	H0YDB7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727242

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.061	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		9.5
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-8.2	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.033	D
Polyphen		0.24	B
Vest4		0.50
MutPred		0.39		Loss of disorder (P = 0.0244)
MVP		0.86
MPC		0.077
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.68
gMVP		0.48
Mutation Taster		=82/18	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: rs917318545; hg19: chr11-87882982;