rs121434310

Variant names:

• chr1-220164733-C-A
• rs121434310
• NM_012414.4:c.3154G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-220164733-C-A
• chr1-220164733-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_012414.4(RAB3GAP2):​c.3154G>T​(p.Gly1052Cys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000689 in 1,451,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. G1052G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RAB3GAP2 NM_012414.4 missense, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 5.61
• 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: ClinGen, Orphanet
• 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 1-220164733-C-A is Pathogenic according to our data. Variant chr1-220164733-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1820.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB3GAP2	NM_012414.4	c.3154G>T	p.Gly1052Cys	missense_variant, splice_region_variant	Exon 27 of 35	ENST00000358951.7	NP_036546.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB3GAP2	ENST00000358951.7	c.3154G>T	p.Gly1052Cys	missense_variant, splice_region_variant	Exon 27 of 35	1	NM_012414.4	ENSP00000351832.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451116 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 720884

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33348

American (AMR) AF: 0.00 AC: 0 AN: 44070

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25894

East Asian (EAS) AF: 0.00 AC: 0 AN: 39530

South Asian (SAS) AF: 0.00 AC: 0 AN: 84930

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52854

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5506

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1105108

Other (OTH) AF: 0.00 AC: 0 AN: 59876

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Martsolf syndrome 1 Pathogenic:1

Apr 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Martsolf syndrome Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	-0.093	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		5.6
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.81		Loss of MoRF binding (P = 0.0856);
MVP		0.78
MPC		0.64
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.94
gMVP		0.75
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.61		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.61		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121434310; hg19: chr1-220338075;