3-129091194-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_198490.3(RAB43):c.541A>G(p.Ile181Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000629 in 1,430,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000063 (0 hom.)
• Consequence: RAB43 NM_198490.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.17

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:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15402219).
• BP6: Variant 3-129091194-T-C is Benign according to our data. Variant chr3-129091194-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3150802.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAB43	NM_198490.3	c.541A>G	p.Ile181Val	missense_variant	3/3	ENST00000315150.10
ISY1-RAB43	NM_001204890.2	c.*192A>G		3_prime_UTR_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAB43	ENST00000315150.10	c.541A>G	p.Ile181Val	missense_variant	3/3	1	NM_198490.3	P1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000629 AC: 9 AN: 1430104 Hom.: 0 Cov.: 28 AF XY: 0.00000282 AC XY: 2 AN XY: 709486

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000245

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: 0.00000641

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome Cov.: 29

Bravo AF: 0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	15
Dann	Uncertain	0.98
DEOGEN2	Benign	0.14	T;T;T;T;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.15	T;T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.60	N;N;N;N;N
MutationTaster	Benign	1.0	D;D;N;N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.20	N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.052	T;T;T;T;T
Sift4G	Benign	0.48	T;T;T;T;T
Polyphen		0.0	B;B;B;B;B
Vest4		0.041
MutPred		0.58		Loss of catalytic residue at I181 (P = 0.1265);Loss of catalytic residue at I181 (P = 0.1265);Loss of catalytic residue at I181 (P = 0.1265);Loss of catalytic residue at I181 (P = 0.1265);Loss of catalytic residue at I181 (P = 0.1265);
MVP		0.95
MPC		1.2
ClinPred		0.10	T
GERP RS		2.8
Varity_R		0.055
gMVP		0.23

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: rs1933624147; hg19: chr3-128810037;