chr17-42128665-T-C

Variant names:

• chr17-42128665-T-C
• rs753989755
• NM_004583.4:c.302A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004583.4(RAB5C):​c.302A>G​(p.Tyr101Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000446 in 1,344,254 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000045 (0 hom.)
• Consequence: RAB5C NM_004583.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.05
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.941

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.302A>G	p.Tyr101Cys	missense	Exon 3 of 6	NP_004574.2
	RAB5C	NM_001252039.2		c.401A>G	p.Tyr134Cys	missense	Exon 4 of 7	NP_001238968.1	P51148-2
	RAB5C	NM_201434.3		c.302A>G	p.Tyr101Cys	missense	Exon 4 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.302A>G	p.Tyr101Cys	missense	Exon 3 of 6	ENSP00000345689.5	P51148-1
	ENSG00000267261	ENST00000592574.1	TSL:5	c.302A>G	p.Tyr101Cys	missense	Exon 3 of 8	ENSP00000468367.1	K7ERQ8
	RAB5C	ENST00000547517.5	TSL:1	c.401A>G	p.Tyr134Cys	missense	Exon 4 of 7	ENSP00000447053.1	P51148-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000120 AC: 2 AN: 166874 AF XY: 0.0000225

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000241

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000446 AC: 6 AN: 1344254 Hom.: 0 Cov.: 32 AF XY: 0.00000757 AC XY: 5 AN XY: 660168

African (AFR) AF: 0.00 AC: 0 AN: 29014

American (AMR) AF: 0.00 AC: 0 AN: 26926

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19674

East Asian (EAS) AF: 0.00 AC: 0 AN: 36174

South Asian (SAS) AF: 0.00 AC: 0 AN: 66798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5248

European-Non Finnish (NFE) AF: 0.00000568 AC: 6 AN: 1056068

Other (OTH) AF: 0.00 AC: 0 AN: 54952

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		6.0
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-8.1	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.83		Loss of phosphorylation at Y101 (P = 0.0626)
MVP		0.66
MPC		1.7
ClinPred		1.0	D
GERP RS		4.1
PromoterAI		-0.0075	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.92
Mutation Taster		=34/66	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.31		Position offset: 5

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

Other links and lift over

dbSNP: rs753989755; hg19: chr17-40280683;