rs1046565

Variant names:

• chr19-18200389-A-G
• rs1046565
• NM_002866.5:c.285T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002866.5(RAB3A):​c.285T>C​(p.Ala95Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.306 in 1,613,350 control chromosomes in the GnomAD database, including 81,309 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (6190 hom., cov: 32)
  • Exomes 𝑓: 0.31 (75119 hom.)
• Consequence: RAB3A NM_002866.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.23
• Publications: 17 publications found

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

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 19-18200389-A-G is Benign according to our data. Variant chr19-18200389-A-G is described in ClinVar as Benign. ClinVar VariationId is 1335855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.23 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.341 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002866.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB3A	NM_002866.5	MANE Select	c.285T>C	p.Ala95Ala	synonymous	Exon 3 of 5	NP_002857.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB3A	ENST00000222256.9	TSL:1 MANE Select	c.285T>C	p.Ala95Ala	synonymous	Exon 3 of 5	ENSP00000222256.3
	RAB3A	ENST00000481914.2	TSL:3	c.285T>C	p.Ala95Ala	synonymous	Exon 3 of 3	ENSP00000472335.1
	RAB3A	ENST00000464076.3	TSL:2	c.-1T>C		5_prime_UTR	Exon 2 of 4	ENSP00000474603.1

Frequencies

GnomAD3 genomes AF: 0.253 AC: 38464 AN: 151996 Hom.: 6189 Cov.: 32

Gnomad AFR AF: 0.0695

Gnomad AMI AF: 0.368

Gnomad AMR AF: 0.265

Gnomad ASJ AF: 0.255

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.471

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.344

Gnomad OTH AF: 0.255

GnomAD2 exomes AF: 0.283 AC: 70967 AN: 251108 AF XY: 0.282

Gnomad AFR exome AF: 0.0626

Gnomad AMR exome AF: 0.268

Gnomad ASJ exome AF: 0.259

Gnomad EAS exome AF: 0.102

Gnomad FIN exome AF: 0.463

Gnomad NFE exome AF: 0.344

Gnomad OTH exome AF: 0.293

GnomAD4 exome AF: 0.312 AC: 455802 AN: 1461236 Hom.: 75119 Cov.: 35 AF XY: 0.309 AC XY: 224400 AN XY: 726922

African (AFR) AF: 0.0562 AC: 1883 AN: 33476

American (AMR) AF: 0.264 AC: 11794 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 6855 AN: 26118

East Asian (EAS) AF: 0.102 AC: 4041 AN: 39688

South Asian (SAS) AF: 0.179 AC: 15407 AN: 86208

European-Finnish (FIN) AF: 0.461 AC: 24625 AN: 53394

Middle Eastern (MID) AF: 0.244 AC: 1408 AN: 5762

European-Non Finnish (NFE) AF: 0.335 AC: 372493 AN: 1111526

Other (OTH) AF: 0.286 AC: 17296 AN: 60380

GnomAD4 genome AF: 0.253 AC: 38470 AN: 152114 Hom.: 6190 Cov.: 32 AF XY: 0.254 AC XY: 18896 AN XY: 74356

African (AFR) AF: 0.0693 AC: 2879 AN: 41532

American (AMR) AF: 0.265 AC: 4050 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 885 AN: 3472

East Asian (EAS) AF: 0.101 AC: 522 AN: 5178

South Asian (SAS) AF: 0.169 AC: 813 AN: 4824

European-Finnish (FIN) AF: 0.471 AC: 4980 AN: 10564

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.344 AC: 23395 AN: 67954

Other (OTH) AF: 0.255 AC: 540 AN: 2114

Alfa AF: 0.308 Hom.: 12162

Bravo AF: 0.230

Asia WGS AF: 0.140 AC: 489 AN: 3478

EpiCase AF: 0.331

EpiControl AF: 0.335

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	2.2
DANN	Benign	0.45
PhyloP100		2.2
Mutation Taster		=295/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1046565; hg19: chr19-18311199; COSMIC: COSV55852088; COSMIC: COSV55852088;