Genetic Variant NM_004703.6:c.655G>C (chr17-5346796-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004703.6(RABEP1):c.655G>C(p.Glu219Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000706 in 1,416,556 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. E219K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

RABEP1
NM_004703.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.49

Publications

0 publications found

Variant links:

Genes affected

RABEP1 (HGNC:17677): (rabaptin, RAB GTPase binding effector protein 1) Enables protein domain specific binding activity and protein homodimerization activity. Involved in vesicle-mediated transport. Located in endocytic vesicle and endosome. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

RABEP1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004703.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RABEP1	NM_004703.6	MANE Select	c.655G>C	p.Glu219Gln	missense	Exon 6 of 18	NP_004694.2
RABEP1	NM_001083585.3		c.655G>C	p.Glu219Gln	missense	Exon 6 of 17	NP_001077054.1	Q15276-2
RABEP1	NM_001291581.2		c.526G>C	p.Glu176Gln	missense	Exon 5 of 17	NP_001278510.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RABEP1	ENST00000537505.6	TSL:1 MANE Select	c.655G>C	p.Glu219Gln	missense	Exon 6 of 18	ENSP00000445408.2	Q15276-1
RABEP1	ENST00000341923.10	TSL:1	c.655G>C	p.Glu219Gln	missense	Exon 6 of 17	ENSP00000339569.6	Q15276-2
RABEP1	ENST00000575475.2	TSL:1	n.691G>C		non_coding_transcript_exon	Exon 5 of 14

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.06e-7

AC:

AN:

1416556

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

702800

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32374

American (AMR)

AF:

0.00

AC:

AN:

40710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24858

East Asian (EAS)

AF:

0.00

AC:

AN:

38642

South Asian (SAS)

AF:

0.0000128

AC:

AN:

77866

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51192

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5584

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1087124

Other (OTH)

AF:

0.00

AC:

AN:

58206

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Uncertain

0.048

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

Eigen

Uncertain

0.63

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.018

MetaRNN

Uncertain

0.55

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.5

PhyloP100

9.5

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-1.0

REVEL

Benign

0.21

Sift

Benign

0.067

Sift4G

Benign

0.080

Polyphen

1.0

Vest4

0.63

MutPred

0.074

Loss of ubiquitination at K218 (P = 0.0731)

MVP

0.45

ClinPred

0.95

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.27

gMVP

0.16

Mutation Taster

=87/13

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over