19-18202619-C-T

Position:

• chr19-18202619-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002866.5(RAB3A):​c.122G>A​(p.Arg41His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAB3A NM_002866.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.80

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]

RAB3A (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAB3A	NM_002866.5	c.122G>A	p.Arg41His	missense_variant	2/5	ENST00000222256.9	NP_002857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAB3A	ENST00000222256.9	c.122G>A	p.Arg41His	missense_variant	2/5	1	NM_002866.5	ENSP00000222256.3
RAB3A	ENST00000481914.2	c.122G>A	p.Arg41His	missense_variant	2/3	3		ENSP00000472335.1
RAB3A	ENST00000464076.3	c.-58+1277G>A		intron_variant		2		ENSP00000474603.1
RAB3A	ENST00000515410.1	n.262G>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Sep 29, 2023

The c.122G>A (p.R41H) alteration is located in exon 2 (coding exon 1) of the RAB3A gene. This alteration results from a G to A substitution at nucleotide position 122, causing the arginine (R) at amino acid position 41 to be replaced by a histidine (H). 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	0.96
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D;D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Pathogenic	3.9	H;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.8	D;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.96
MutPred		0.90		Loss of catalytic residue at R41 (P = 0.0663);Loss of catalytic residue at R41 (P = 0.0663);
MVP		0.91
MPC		2.1
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.85
gMVP		0.94

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: chr19-18313429;