chr19-18197483-T-G

Position:

• chr19-18197483-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002866.5(RAB3A):​c.650A>C​(p.Asp217Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,176 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: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RAB3A NM_002866.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.68

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2679026).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAB3A	NM_002866.5	c.650A>C	p.Asp217Ala	missense_variant	5/5	ENST00000222256.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAB3A	ENST00000222256.9	c.650A>C	p.Asp217Ala	missense_variant	5/5	1	NM_002866.5	P1
RAB3A	ENST00000464076.3	c.365A>C	p.Asp122Ala	missense_variant	4/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460176 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726346

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.: 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

Dec 08, 2023

The c.650A>C (p.D217A) alteration is located in exon 5 (coding exon 4) of the RAB3A gene. This alteration results from a A to C substitution at nucleotide position 650, causing the aspartic acid (D) at amino acid position 217 to be replaced by an alanine (A). 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	Benign	0.14
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	22
DANN	Uncertain	0.97
DEOGEN2	Benign	0.37	T;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.59	T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.59	N;.
REVEL	Uncertain	0.34
Sift	Benign	0.37	T;.
Sift4G	Benign	0.49	T;T
Polyphen		0.0	B;.
Vest4		0.17
MutPred		0.24		Gain of glycosylation at P214 (P = 0.0923);.;
MVP		0.86
MPC		1.1
ClinPred		0.54	D
GERP RS		3.9
Varity_R		0.17
gMVP		0.55

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: rs1600026726; hg19: chr19-18308293;