chr12-55987006-A-G

Variant names:

• chr12-55987006-A-G
• rs757683306
• NM_002868.4:c.46A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002868.4(RAB5B):​c.46A>G​(p.Ser16Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,551,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 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. S16N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000069 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: RAB5B NM_002868.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.12
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15123338).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB5B	NM_002868.4	c.46A>G	p.Ser16Gly	missense_variant	Exon 2 of 6	ENST00000360299.10	NP_002859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB5B	ENST00000360299.10	c.46A>G	p.Ser16Gly	missense_variant	Exon 2 of 6	1	NM_002868.4	ENSP00000353444.5

Frequencies

GnomAD3 genomes AF: 0.00000690 AC: 1 AN: 144852 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000716

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

GnomAD2 exomes AF: 0.0000636 AC: 16 AN: 251456 AF XY: 0.0000368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000107 AC: 15 AN: 1406762 Hom.: 0 Cov.: 34 AF XY: 0.00000715 AC XY: 5 AN XY: 699162

African (AFR) AF: 0.00 AC: 0 AN: 31888

American (AMR) AF: 0.000350 AC: 15 AN: 42854

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24200

East Asian (EAS) AF: 0.00 AC: 0 AN: 35092

South Asian (SAS) AF: 0.00 AC: 0 AN: 85700

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48946

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5482

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1075954

Other (OTH) AF: 0.00 AC: 0 AN: 56646

GnomAD4 genome AF: 0.00000690 AC: 1 AN: 144852 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 70172

African (AFR) AF: 0.00 AC: 0 AN: 39480

American (AMR) AF: 0.0000716 AC: 1 AN: 13972

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3408

East Asian (EAS) AF: 0.00 AC: 0 AN: 4528

South Asian (SAS) AF: 0.00 AC: 0 AN: 4368

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66532

Other (OTH) AF: 0.00 AC: 0 AN: 2020

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000576 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 11, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.46A>G (p.S16G) alteration is located in exon 2 (coding exon 1) of the RAB5B gene. This alteration results from a A to G substitution at nucleotide position 46, causing the serine (S) at amino acid position 16 to be replaced by a glycine (G). 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	0.077
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.037	T;T;T;T;T;.;T
Eigen	Benign	-0.029
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	.;D;D;D;D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.15	T;T;T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.70	N;N;.;.;.;N;.
PhyloP100		9.1
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.29	N;N;N;N;N;N;.
REVEL	Benign	0.17
Sift	Benign	0.12	T;T;T;T;T;T;.
Sift4G	Benign	0.29	T;T;T;T;T;T;T
Polyphen		0.0	B;B;.;.;.;.;.
Vest4		0.22
MutPred		0.39		Loss of stability (P = 0.072);Loss of stability (P = 0.072);Loss of stability (P = 0.072);.;Loss of stability (P = 0.072);Loss of stability (P = 0.072);Loss of stability (P = 0.072);
MVP		0.70
MPC		0.61
ClinPred		0.15	T
GERP RS		4.9
PromoterAI		-0.032	Neutral
Varity_R		0.22
gMVP		0.35
Mutation Taster		=73/27	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: rs757683306; hg19: chr12-56380790;