17-42125877-T-A

Position:

• chr17-42125877-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000346213.9(RAB5C):​c.557A>T​(p.Glu186Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RAB5C ENST00000346213.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.00

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29695794).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAB5C	NM_004583.4	c.557A>T	p.Glu186Val	missense_variant	6/6	ENST00000346213.9	NP_004574.2
RAB5C	NM_001252039.2	c.656A>T	p.Glu219Val	missense_variant	7/7		NP_001238968.1
RAB5C	NM_201434.3	c.557A>T	p.Glu186Val	missense_variant	7/7		NP_958842.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAB5C	ENST00000346213.9	c.557A>T	p.Glu186Val	missense_variant	6/6	1	NM_004583.4	ENSP00000345689.5
ENSG00000267261	ENST00000592574.1	c.441+2384A>T		intron_variant		5		ENSP00000468367.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2022

The c.557A>T (p.E186V) alteration is located in exon 7 (coding exon 5) of the RAB5C gene. This alteration results from a A to T substitution at nucleotide position 557, causing the glutamic acid (E) at amino acid position 186 to be replaced by a valine (V). 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	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;T;.
Eigen	Benign	-0.044
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	.;D;D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.30	T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.55	N;N;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Uncertain	0.57
Sift	Benign	0.042	D;D;D
Sift4G	Benign	0.13	T;T;T
Polyphen		0.18	B;B;.
Vest4		0.48
MutPred		0.30		Gain of MoRF binding (P = 0.0148);Gain of MoRF binding (P = 0.0148);.;
MVP		0.91
MPC		0.73
ClinPred		0.98	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.44
gMVP		0.56

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: chr17-40277895;