Genetic Variant RAB5B:c.438+99T>C (chr12-55990903-T-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The NM_002868.4(RAB5B):c.438+99T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.303 in 1,427,948 control chromosomes in the GnomAD database, including 68,954 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.24 ( 5149 hom., cov: 32)

Exomes 𝑓: 0.31 ( 63805 hom. )

Consequence

RAB5B
NM_002868.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.25

Publications

28 publications found

Variant links:

Genes affected

RAB5B (HGNC:9784): (RAB5B, member RAS oncogene family) Enables GDP binding activity; GTP-dependent protein binding activity; and GTPase activity. Involved in antigen processing and presentation and plasma membrane to endosome transport. Located in endosome and extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

RAB5B links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.19).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.317 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB5B	NM_002868.4 link	c.438+99T>C		intron_variant	Intron 4 of 5	ENST00000360299.10	NP_002859.1	P61020-1A0A024RB09

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB5B	ENST00000360299.10 link	c.438+99T>C		intron_variant	Intron 4 of 5	1	NM_002868.4	ENSP00000353444.5		P61020-1

Frequencies

GnomAD3 genomes

AF:

0.240

AC:

36481

AN:

151984

Hom.:

5150

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0897

Gnomad AMI

AF:

0.513

Gnomad AMR

AF:

0.229

Gnomad ASJ

AF:

0.325

Gnomad EAS

AF:

0.226

Gnomad SAS

AF:

0.218

Gnomad FIN

AF:

0.286

Gnomad MID

AF:

0.237

Gnomad NFE

AF:

0.321

Gnomad OTH

AF:

0.261

GnomAD4 exome

AF:

0.311

AC:

396570

AN:

1275846

Hom.:

63805

Cov.:

AF XY:

0.309

AC XY:

195558

AN XY:

633828

show subpopulations

African (AFR)

AF:

0.0802

AC:

2320

AN:

28936

American (AMR)

AF:

0.211

AC:

7929

AN:

37574

Ashkenazi Jewish (ASJ)

AF:

0.321

AC:

6813

AN:

21194

East Asian (EAS)

AF:

0.211

AC:

7924

AN:

37558

South Asian (SAS)

AF:

0.225

AC:

16804

AN:

74838

European-Finnish (FIN)

AF:

0.295

AC:

14319

AN:

48550

Middle Eastern (MID)

AF:

0.231

AC:

867

AN:

3760

European-Non Finnish (NFE)

AF:

0.334

AC:

323962

AN:

970446

Other (OTH)

AF:

0.295

AC:

15632

AN:

52990

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

12567

25133

37700

50266

62833

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10348

20696

31044

41392

51740

<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

AF:

0.240

AC:

36483

AN:

152102

Hom.:

5149

Cov.:

AF XY:

0.237

AC XY:

17585

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.0895

AC:

3718

AN:

41536

American (AMR)

AF:

0.229

AC:

3498

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.325

AC:

1126

AN:

3468

East Asian (EAS)

AF:

0.225

AC:

1166

AN:

5172

South Asian (SAS)

AF:

0.219

AC:

1056

AN:

4818

European-Finnish (FIN)

AF:

0.286

AC:

3024

AN:

10576

Middle Eastern (MID)

AF:

0.241

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.321

AC:

21813

AN:

67960

Other (OTH)

AF:

0.259

AC:

545

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1344

2689

4033

5378

6722

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

384

768

1152

1536

1920

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.251

Hom.:

1513

Bravo

AF:

0.232

Asia WGS

AF:

0.178

AC:

622

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Benign

0.84

PhyloP100

1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over