rs149842844

Variant names:

• chr1-220151641-G-T
• rs149842844
• NM_012414.4:c.3991C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_012414.4(RAB3GAP2):​c.3991C>A​(p.Leu1331Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000573 in 1,612,332 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00058 (3 hom.)
• Consequence: RAB3GAP2 NM_012414.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.60
• Publications: 4 publications found

Genes affected

RAB3GAP2 (HGNC:17168): (RAB3 GTPase activating non-catalytic protein subunit 2) The protein encoded by this gene belongs to the RAB3 protein family, members of which are involved in regulated exocytosis of neurotransmitters and hormones. This protein forms the Rab3 GTPase-activating complex with RAB3GAP1, where it constitutes the regulatory subunit, whereas the latter functions as the catalytic subunit. This gene has the highest level of expression in the brain, consistent with it having a key role in neurodevelopment. Mutations in this gene are associated with Martsolf syndrome.[provided by RefSeq, Oct 2009]

RAB3GAP2 Gene-Disease associations (from GenCC):

• Martsolf syndrome 1

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• RAB18 deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
• Warburg micro syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Warburg micro syndrome 2

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• autosomal recessive spastic paraplegia type 69

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• cataract-intellectual disability-hypogonadism syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015336275).
• BP6: Variant 1-220151641-G-T is Benign according to our data. Variant chr1-220151641-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 287195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000486 (74/152294) while in subpopulation AMR AF = 0.00262 (40/15288). AF 95% confidence interval is 0.00197. There are 0 homozygotes in GnomAd4. There are 41 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012414.4. 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
	RAB3GAP2	NM_012414.4	MANE Select	c.3991C>A	p.Leu1331Ile	missense	Exon 34 of 35	NP_036546.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB3GAP2	ENST00000358951.7	TSL:1 MANE Select	c.3991C>A	p.Leu1331Ile	missense	Exon 34 of 35	ENSP00000351832.2	Q9H2M9-1
	RAB3GAP2	ENST00000692972.1		c.4066C>A	p.Leu1356Ile	missense	Exon 35 of 36	ENSP00000510753.1	A0A8I5KZB3
	RAB3GAP2	ENST00000691661.1		c.4003C>A	p.Leu1335Ile	missense	Exon 34 of 35	ENSP00000510185.1	A0A8I5KYQ0

Frequencies

GnomAD3 genomes AF: 0.000486 AC: 74 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000855 AC: 215 AN: 251334 AF XY: 0.000699

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00387

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000484

Gnomad OTH exome AF: 0.00407

GnomAD4 exome AF: 0.000582 AC: 850 AN: 1460038 Hom.: 3 Cov.: 31 AF XY: 0.000559 AC XY: 406 AN XY: 726422

African (AFR) AF: 0.00 AC: 0 AN: 33426

American (AMR) AF: 0.00418 AC: 187 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86216

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000556 AC: 617 AN: 1110338

Other (OTH) AF: 0.000663 AC: 40 AN: 60346

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.000551 AC XY: 41 AN XY: 74468

African (AFR) AF: 0.0000481 AC: 2 AN: 41566

American (AMR) AF: 0.00262 AC: 40 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68028

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000536 Hom.: 1

Bravo AF: 0.000865

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000832 AC: 101

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Martsolf syndrome (1)
-	-	1	Martsolf syndrome;C3280214:Warburg micro syndrome 2 (1)
-	-	1	not provided (1)
-	-	1	RAB3GAP2-related disorder (1)
-	-	1	Warburg micro syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.094
Eigen_PC	Benign	-0.15
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.6
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.11
Sift	Benign	0.24	T
Sift4G	Uncertain	0.018	D
Polyphen		0.70	P
Vest4		0.70
MVP		0.39
MPC		0.41
ClinPred		0.076	T
GERP RS		2.9
Varity_R		0.15
gMVP		0.29
Mutation Taster		=88/12	polymorphism

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: rs149842844; hg19: chr1-220324983; COSMIC: COSV56958588; COSMIC: COSV56958588;