chr17-42125841-C-T

Variant names:

• chr17-42125841-C-T
• rs782559570
• NM_004583.4:c.593G>A

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.593G>A​(p.Arg198Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000116 in 1,459,578 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: RAB5C NM_004583.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.06
• Publications: 1 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=0.16899791).

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.593G>A	p.Arg198Gln	missense	Exon 6 of 6	NP_004574.2
	RAB5C	NM_001252039.2		c.692G>A	p.Arg231Gln	missense	Exon 7 of 7	NP_001238968.1	P51148-2
	RAB5C	NM_201434.3		c.593G>A	p.Arg198Gln	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.593G>A	p.Arg198Gln	missense	Exon 6 of 6	ENSP00000345689.5	P51148-1
	RAB5C	ENST00000547517.5	TSL:1	c.692G>A	p.Arg231Gln	missense	Exon 7 of 7	ENSP00000447053.1	P51148-2
	RAB5C	ENST00000393860.7	TSL:1	c.593G>A	p.Arg198Gln	missense	Exon 7 of 7	ENSP00000377440.3	P51148-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000162 AC: 4 AN: 246306 AF XY: 0.0000150

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1459578 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 725742

African (AFR) AF: 0.0000598 AC: 2 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44432

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26036

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 85526

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53178

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111204

Other (OTH) AF: 0.0000332 AC: 2 AN: 60326

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.033	T
Eigen	Benign	-0.073
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.81	L
PhyloP100		6.1
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.068
Sift	Benign	0.24	T
Sift4G	Benign	0.68	T
Polyphen		0.66	P
Vest4		0.36
MutPred		0.29		Loss of methylation at R198 (P = 0.0707)
MVP		0.53
MPC		0.70
ClinPred		0.23	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.43
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs782559570; hg19: chr17-40277859;