19-18200427-G-A

Variant names:

• chr19-18200427-G-A
• rs751734980
• NM_002866.5:c.247C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_002866.5(RAB3A):​c.247C>T​(p.Arg83Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAB3A NM_002866.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.54

Genes affected

RAB3A (HGNC:9777): (RAB3A, member RAS oncogene family) Enables GTPase activity and myosin V binding activity. Involved in several processes, including acrosomal vesicle exocytosis; lysosome localization; and plasma membrane repair. Located in perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 19-18200427-G-A is Pathogenic according to our data. Variant chr19-18200427-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3359236.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB3A	NM_002866.5	c.247C>T	p.Arg83Trp	missense_variant	Exon 3 of 5	ENST00000222256.9	NP_002857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB3A	ENST00000222256.9	c.247C>T	p.Arg83Trp	missense_variant	Exon 3 of 5	1	NM_002866.5	ENSP00000222256.3
RAB3A	ENST00000481914.2	c.247C>T	p.Arg83Trp	missense_variant	Exon 3 of 3	3		ENSP00000472335.1
RAB3A	ENST00000464076.3	c.-39C>T		5_prime_UTR_variant	Exon 2 of 4	2		ENSP00000474603.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

RAB3A-related condition Pathogenic:1

Apr 21, 2023

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Pathogenic	4.3	H;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-7.4	D;.
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.92
MutPred		0.90		Loss of disorder (P = 0.0495);Loss of disorder (P = 0.0495);
MVP		0.85
MPC		2.1
ClinPred		1.0	D
GERP RS		1.6
Varity_R		0.71
gMVP		0.90

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: rs751734980; hg19: chr19-18311237; COSMIC: COSV55853701; COSMIC: COSV55853701;