chr17-28714853-C-T

Variant names:

• chr17-28714853-C-T
• NM_031934.6:c.652G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_031934.6(RAB34):​c.652G>A​(p.Glu218Lys) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAB34 NM_031934.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.56
• Publications: 0 publications found

Genes affected

RAB34 (HGNC:16519): (RAB34, member RAS oncogene family) This gene encodes a protein belonging to the RAB family of proteins, which are small GTPases involved in protein transport. This family member is a Golgi-bound member of the secretory pathway that is involved in the repositioning of lysosomes and the activation of macropinocytosis. Alternative splicing of this gene results in multiple transcript variants. An alternatively spliced transcript variant produces the nine-amino acid residue-repeats (NARR) protein, which is a functionally distinct nucleolar protein resulting from a different reading frame. [provided by RefSeq, Dec 2016]

RAB34 Gene-Disease associations (from GenCC):

• orofaciodigital syndrome 20

  Inheritance: AR Classification: MODERATE Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.849
• PP5: Variant 17-28714853-C-T is Pathogenic according to our data. Variant chr17-28714853-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2921270.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031934.6. 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
	RAB34	NM_031934.6	MANE Select	c.652G>A	p.Glu218Lys	missense	Exon 9 of 10	NP_114140.4
	RAB34	NM_001144943.1		c.823G>A	p.Glu275Lys	missense	Exon 10 of 11	NP_001138415.1	B4DNC0
	RAB34	NM_001142624.2		c.799G>A	p.Glu267Lys	missense	Exon 10 of 11	NP_001136096.2	B4DNC0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB34	ENST00000395245.9	TSL:1 MANE Select	c.652G>A	p.Glu218Lys	missense	Exon 9 of 10	ENSP00000378666.3	Q9BZG1-1
	RAB34	ENST00000301043.10	TSL:1	c.652G>A	p.Glu218Lys	missense	Exon 10 of 11	ENSP00000301043.6	Q9BZG1-1
	RAB34	ENST00000395243.7	TSL:1	c.*476G>A		3_prime_UTR	Exon 9 of 10	ENSP00000378664.4	A0A1C7CYW6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Orofaciodigital syndrome 20 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Benign	0.083	T
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.062	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.8	L
PhyloP100		7.6
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.088	T
Polyphen		1.0	D
Vest4		0.84
MVP		0.90
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.57
Mutation Taster		=39/61	disease causing

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

hg19: chr17-27041871;