14-24267755-T-C

Variant names:

• chr14-24267755-T-C
• rs729421
• NM_182836.3:c.1258A>G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.50 (20653 hom., cov: 33)
  • Exomes 𝑓: 0.41 (126251 hom.)
• Consequence: RABGGTA NM_182836.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.99

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]

ACMG classification

Verdict is Benign. Variant got -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	c.1258A>G	p.Thr420Ala	missense_variant	Exon 14 of 17	ENST00000216840.11	NP_878256.1
RABGGTA	NM_004581.5	c.1258A>G	p.Thr420Ala	missense_variant	Exon 13 of 16		NP_004572.3

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.498 AC: 75687 AN: 151936 Hom.: 20619 Cov.: 33

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

GnomAD3 exomes AF: 0.465 AC: 115550 AN: 248490 Hom.: 28580 AF XY: 0.460 AC XY: 61951 AN XY: 134804

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 SAS exome AF: 0.575

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.: 47 AF XY: 0.410 AC XY: 297696 AN XY: 726032

Gnomad4 AFR exome AF: 0.732

Gnomad4 AMR exome AF: 0.563

Gnomad4 ASJ exome AF: 0.462

Gnomad4 EAS exome AF: 0.612

Gnomad4 SAS exome AF: 0.570

Gnomad4 FIN exome AF: 0.366

Gnomad4 NFE exome AF: 0.370

Gnomad4 OTH exome AF: 0.427

GnomAD4 genome AF: 0.498 AC: 75777 AN: 152056 Hom.: 20653 Cov.: 33 AF XY: 0.501 AC XY: 37259 AN XY: 74342

Gnomad4 AFR AF: 0.721

Gnomad4 AMR AF: 0.517

Gnomad4 ASJ AF: 0.443

Gnomad4 EAS AF: 0.595

Gnomad4 SAS AF: 0.585

Gnomad4 FIN AF: 0.363

Gnomad4 NFE AF: 0.372

Gnomad4 OTH AF: 0.473

Alfa AF: 0.408 Hom.: 29713

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	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	16
DANN	Benign	0.70
DEOGEN2	Benign	0.082	T;T;.
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.041	N
MetaRNN	Benign	0.0000015	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-2.0	N;N;.
PrimateAI	Benign	0.46	T
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	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.031
gMVP		0.19

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

LitVar

Other links and lift over

dbSNP: rs729421; hg19: chr14-24736961; COSMIC: COSV52861986; COSMIC: COSV52861986;