Genetic Variant RAB34:p.Arg211Pro (chr17-28714873-C-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_031934.6(RAB34):c.632G>C(p.Arg211Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R211H) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RAB34
NM_031934.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.58

Publications

0 publications found

Variant links:

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

RAB34 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-28714873-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2921273.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.92

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RAB34	NM_031934.6	MANE Select	c.632G>C	p.Arg211Pro	missense	Exon 9 of 10	NP_114140.4
RAB34	NM_001144943.1		c.803G>C	p.Arg268Pro	missense	Exon 10 of 11	NP_001138415.1	B4DNC0
RAB34	NM_001142624.2		c.779G>C	p.Arg260Pro	missense	Exon 10 of 11	NP_001136096.2	B4DNC0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RAB34	ENST00000395245.9	TSL:1 MANE Select	c.632G>C	p.Arg211Pro	missense	Exon 9 of 10	ENSP00000378666.3	Q9BZG1-1
RAB34	ENST00000301043.10	TSL:1	c.632G>C	p.Arg211Pro	missense	Exon 10 of 11	ENSP00000301043.6	Q9BZG1-1
RAB34	ENST00000395243.7	TSL:1	c.*456G>C		3_prime_UTR	Exon 9 of 10	ENSP00000378664.4	A0A1C7CYW6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251378

AF XY:

0.00000736

show subpopulations

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461798

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727194

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53350

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111990

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

(source)

DANN

Benign

0.93

DEOGEN2

Uncertain

0.68

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

0.67

MutationAssessor

Pathogenic

3.0

PhyloP100

7.6

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-6.0

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.90

MVP

0.96

ClinPred

1.0

GERP RS

5.5

Varity_R

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over