3-129121432-T-C

Position:

• chr3-129121432-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_198490.3(RAB43):​c.58A>G​(p.Lys20Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,086 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.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RAB43 NM_198490.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.64

Genes affected

RAB43 (HGNC:19983): (RAB43, member RAS oncogene family) Enables GTPase activity. Involved in several processes, including Golgi organization; phagosome maturation; and retrograde transport, plasma membrane to Golgi. Located in Golgi apparatus and phagocytic vesicle. [provided by Alliance of Genome Resources, Apr 2022]

ISY1-RAB43 (HGNC:42969): (ISY1-RAB43 readthrough) This locus represents naturally occurring read-through transcription between the neighboring ISY1 (ISY1 splicing factor homolog) and RAB43 (RAB43, member RAS oncogene family) gene on chromosome 3. The read-through transcript encodes a protein that shares sequence identity with the upstream gene product, but its C-terminus is distinct due to a frameshift relative to the downstream gene. [provided by RefSeq, Mar 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.89

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAB43	NM_198490.3	c.58A>G	p.Lys20Glu	missense_variant	1/3	ENST00000315150.10	NP_940892.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAB43	ENST00000315150.10	c.58A>G	p.Lys20Glu	missense_variant	1/3	1	NM_198490.3	ENSP00000319781.6
ISY1-RAB43	ENST00000418265.1	c.851+8656A>G		intron_variant		2		ENSP00000411822.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461086 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726860

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2024

The c.58A>G (p.K20E) alteration is located in exon 1 (coding exon 1) of the RAB43 gene. This alteration results from a A to G substitution at nucleotide position 58, causing the lysine (K) at amino acid position 20 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T;T;T;T;T;.;.;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.95	.;.;.;.;D;.;D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	4.0	H;H;H;H;H;H;H;.
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-3.6	D;D;D;D;D;D;.;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D;D;D;D;D;D;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;.
Polyphen		0.90	P;P;P;P;P;.;.;.
Vest4		0.82
MutPred		0.69		Loss of methylation at K20 (P = 6e-04);Loss of methylation at K20 (P = 6e-04);Loss of methylation at K20 (P = 6e-04);Loss of methylation at K20 (P = 6e-04);Loss of methylation at K20 (P = 6e-04);Loss of methylation at K20 (P = 6e-04);Loss of methylation at K20 (P = 6e-04);Loss of methylation at K20 (P = 6e-04);
MVP		0.94
MPC		2.3
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.90
gMVP		0.97

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-128840275;