17-42125805-C-A

Variant names:

• chr17-42125805-C-A
• rs1366208306
• NM_004583.4:c.629G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004583.4(RAB5C):​c.629G>T​(p.Arg210Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign 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. R210Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RAB5C NM_004583.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.28
• Publications: 0 publications found

Genes affected

RAB5C (HGNC:9785): (RAB5C, member RAS oncogene family) Members of the Rab protein family are small GTPases of the Ras superfamily that are thought to ensure fidelity in the process of docking and/or fusion of vesicles with their correct acceptor compartment (Han et al., 1996 [PubMed 8646882]).[supplied by OMIM, Nov 2010]

ENSG00000267261 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14324835).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004583.4. 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
	RAB5C	NM_004583.4	MANE Select	c.629G>T	p.Arg210Leu	missense	Exon 6 of 6	NP_004574.2
	RAB5C	NM_001252039.2		c.728G>T	p.Arg243Leu	missense	Exon 7 of 7	NP_001238968.1	P51148-2
	RAB5C	NM_201434.3		c.629G>T	p.Arg210Leu	missense	Exon 7 of 7	NP_958842.1	P51148-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB5C	ENST00000346213.9	TSL:1 MANE Select	c.629G>T	p.Arg210Leu	missense	Exon 6 of 6	ENSP00000345689.5	P51148-1
	RAB5C	ENST00000547517.5	TSL:1	c.728G>T	p.Arg243Leu	missense	Exon 7 of 7	ENSP00000447053.1	P51148-2
	RAB5C	ENST00000393860.7	TSL:1	c.629G>T	p.Arg210Leu	missense	Exon 7 of 7	ENSP00000377440.3	P51148-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455458 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 723310

⚠️ 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: 33418

American (AMR) AF: 0.00 AC: 0 AN: 43874

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25900

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39536

South Asian (SAS) AF: 0.00 AC: 0 AN: 84910

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109414

Other (OTH) AF: 0.00 AC: 0 AN: 60158

⚠️ 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.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.20
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.3
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.20
Sift	Benign	0.099	T
Sift4G	Benign	0.10	T
Polyphen		0.093	B
Vest4		0.27
MutPred		0.25		Loss of catalytic residue at R210 (P = 0.1002)
MVP		0.60
MPC		0.74
ClinPred		0.79	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.59
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1366208306; hg19: chr17-40277823;