12-55990788-G-T

Variant names:

• chr12-55990788-G-T
• rs778468588
• NM_002868.4:c.422G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002868.4(RAB5B):​c.422G>T​(p.Arg141Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 152,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R141H) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.000020 (0 hom., cov: 32)
• Consequence: RAB5B NM_002868.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.08
• Publications: 0 publications found

Genes affected

RAB5B (HGNC:9784): (RAB5B, member RAS oncogene family) Enables GDP binding activity; GTP-dependent protein binding activity; and GTPase activity. Involved in antigen processing and presentation and plasma membrane to endosome transport. Located in endosome and extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB5B	NM_002868.4	c.422G>T	p.Arg141Leu	missense_variant	Exon 4 of 6	ENST00000360299.10	NP_002859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB5B	ENST00000360299.10	c.422G>T	p.Arg141Leu	missense_variant	Exon 4 of 6	1	NM_002868.4	ENSP00000353444.5

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74380

African (AFR) AF: 0.0000724 AC: 3 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Uncertain	2.8	M;M
PhyloP100		8.1
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.3	D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.93
MutPred		0.72		Loss of disorder (P = 0.0825);Loss of disorder (P = 0.0825);
MVP		0.93
MPC		1.7
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.88
gMVP		0.77
Mutation Taster		=51/49	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.21		Position offset: 4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs778468588; hg19: chr12-56384572;