3-129121293-C-A

Variant names:

• chr3-129121293-C-A
• rs377487313
• NM_198490.3:c.197G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_198490.3(RAB43):​c.197G>T​(p.Arg66Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000028 in 1,604,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: RAB43 NM_198490.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.07
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10929045).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198490.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB43	NM_198490.3	MANE Select	c.197G>T	p.Arg66Leu	missense	Exon 1 of 3	NP_940892.1	Q86YS6-1
	RAB43	NM_001204883.2		c.197G>T	p.Arg66Leu	missense	Exon 2 of 4	NP_001191812.1	Q86YS6-1
	RAB43	NM_001204884.2		c.197G>T	p.Arg66Leu	missense	Exon 2 of 4	NP_001191813.1	Q86YS6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB43	ENST00000315150.10	TSL:1 MANE Select	c.197G>T	p.Arg66Leu	missense	Exon 1 of 3	ENSP00000319781.6	Q86YS6-1
	ISY1-RAB43	ENST00000418265.1	TSL:2	c.851+8795G>T		intron	N/A	ENSP00000411822.1
	RAB43	ENST00000915979.1		c.197G>T	p.Arg66Leu	missense	Exon 2 of 5	ENSP00000586038.1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000478 AC: 11 AN: 229972 AF XY: 0.0000400

Gnomad AFR exome AF: 0.000707

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000977

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000117 AC: 17 AN: 1452786 Hom.: 0 Cov.: 31 AF XY: 0.0000111 AC XY: 8 AN XY: 721970

African (AFR) AF: 0.000420 AC: 14 AN: 33330

American (AMR) AF: 0.0000232 AC: 1 AN: 43142

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25844

East Asian (EAS) AF: 0.00 AC: 0 AN: 39374

South Asian (SAS) AF: 0.00 AC: 0 AN: 84522

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108294

Other (OTH) AF: 0.0000333 AC: 2 AN: 60054

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152182 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74330

African (AFR) AF: 0.000603 AC: 25 AN: 41446

American (AMR) AF: 0.000131 AC: 2 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000200

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000495 AC: 6

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.1
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.36
Sift	Benign	0.11	T
Sift4G	Benign	0.17	T
Polyphen		0.98	D
Vest4		0.37
MVP		0.80
MPC		1.8
ClinPred		0.11	T
GERP RS		2.3
PromoterAI		-0.0020	Neutral
Varity_R		0.49
gMVP		0.73
Mutation Taster		=28/72	disease causing

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

Other links and lift over

dbSNP: rs377487313; hg19: chr3-128840136;