Genetic Variant RABGGTA:p.Thr420Ala (chr14-24267755-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_182836.3(RABGGTA):c.1258A>G(p.Thr420Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.415 in 1,611,486 control chromosomes in the GnomAD database, including 146,904 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.50 ( 20653 hom., cov: 33)

Exomes 𝑓: 0.41 ( 126251 hom. )

Consequence

RABGGTA
NM_182836.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.99

Publications

46 publications found

Variant links:

Genes affected

RABGGTA (HGNC:9795): (Rab geranylgeranyltransferase subunit alpha) Predicted to enable small GTPase binding activity. Predicted to contribute to Rab geranylgeranyltransferase activity. Predicted to be involved in protein geranylgeranylation. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

RABGGTA links:

ENSG00000288044 (HGNC:):

ENSG00000288044 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.4918523E-6).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.714 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RABGGTA	NM_182836.3 link	c.1258A>G	p.Thr420Ala	missense_variant	Exon 14 of 17	ENST00000216840.11	NP_878256.1	Q92696
RABGGTA	NM_004581.5 link	c.1258A>G	p.Thr420Ala	missense_variant	Exon 13 of 16		NP_004572.3	Q92696

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RABGGTA	ENST00000216840.11 link	c.1258A>G	p.Thr420Ala	missense_variant	Exon 14 of 17	1	NM_182836.3	ENSP00000216840.6		Q92696

Frequencies

GnomAD3 genomes

AF:

0.498

AC:

75687

AN:

151936

Hom.:

20619

Cov.:

show subpopulations

Gnomad AFR

AF:

0.721

Gnomad AMI

AF:

0.332

Gnomad AMR

AF:

0.517

Gnomad ASJ

AF:

0.443

Gnomad EAS

AF:

0.595

Gnomad SAS

AF:

0.586

Gnomad FIN

AF:

0.363

Gnomad MID

AF:

0.357

Gnomad NFE

AF:

0.372

Gnomad OTH

AF:

0.469

GnomAD2 exomes

AF:

0.465

AC:

115550

AN:

248490

AF XY:

0.460

show subpopulations

Gnomad AFR exome

AF:

0.727

Gnomad AMR exome

AF:

0.568

Gnomad ASJ exome

AF:

0.456

Gnomad EAS exome

AF:

0.599

Gnomad FIN exome

AF:

0.363

Gnomad NFE exome

AF:

0.368

Gnomad OTH exome

AF:

0.436

GnomAD4 exome

AF:

0.406

AC:

593132

AN:

1459430

Hom.:

126251

Cov.:

AF XY:

0.410

AC XY:

297696

AN XY:

726032

show subpopulations

African (AFR)

AF:

0.732

AC:

24467

AN:

33410

American (AMR)

AF:

0.563

AC:

25142

AN:

44650

Ashkenazi Jewish (ASJ)

AF:

0.462

AC:

12063

AN:

26128

East Asian (EAS)

AF:

0.612

AC:

24270

AN:

39688

South Asian (SAS)

AF:

0.570

AC:

49109

AN:

86152

European-Finnish (FIN)

AF:

0.366

AC:

19539

AN:

53372

Middle Eastern (MID)

AF:

0.435

AC:

1951

AN:

4490

European-Non Finnish (NFE)

AF:

0.370

AC:

410858

AN:

1111324

Other (OTH)

AF:

0.427

AC:

25733

AN:

60216

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

18516

37031

55547

74062

92578

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13354

26708

40062

53416

66770

<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:

0.498

AC:

75777

AN:

152056

Hom.:

20653

Cov.:

AF XY:

0.501

AC XY:

37259

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.721

AC:

29908

AN:

41474

American (AMR)

AF:

0.517

AC:

7898

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.443

AC:

1538

AN:

3472

East Asian (EAS)

AF:

0.595

AC:

3068

AN:

5160

South Asian (SAS)

AF:

0.585

AC:

2815

AN:

4816

European-Finnish (FIN)

AF:

0.363

AC:

3844

AN:

10592

Middle Eastern (MID)

AF:

0.350

AC:

103

AN:

294

European-Non Finnish (NFE)

AF:

0.372

AC:

25303

AN:

67942

Other (OTH)

AF:

0.473

AC:

997

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1826

3652

5477

7303

9129

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

662

1324

1986

2648

3310

<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:

0.429

Hom.:

51701

Bravo

AF:

0.520

TwinsUK

AF:

0.362

AC:

1344

ALSPAC

AF:

0.366

AC:

1410

ESP6500AA

AF:

0.694

AC:

3015

ESP6500EA

AF:

0.372

AC:

3175

ExAC

AF:

0.466

AC:

56470

Asia WGS

AF:

0.608

AC:

2114

AN:

3478

EpiCase

AF:

0.380

EpiControl

AF:

0.371

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.043

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.082

T;T;.

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.041

MetaRNN

Benign

0.0000015

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-2.0

N;N;.

PhyloP100

2.0

PrimateAI

Benign

0.46

PROVEAN

Benign

0.96

N;N;N

REVEL

Benign

0.067

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.045

MPC

0.12

ClinPred

0.000011

GERP RS

3.7

PromoterAI

-0.018

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.031

gMVP

0.19

Mutation Taster

=99/1

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over