chr1-220164733-C-T

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_012414.4(RAB3GAP2):​c.3154G>A​(p.Gly1052Ser) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1052C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RAB3GAP2 NM_012414.4 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.61
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.3154G>A	p.Gly1052Ser	missense splice_region	Exon 27 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.3154G>A	p.Gly1052Ser	missense splice_region	Exon 27 of 35	ENSP00000351832.2	Q9H2M9-1
	RAB3GAP2	ENST00000692972.1		c.3229G>A	p.Gly1077Ser	missense splice_region	Exon 28 of 36	ENSP00000510753.1	A0A8I5KZB3
	RAB3GAP2	ENST00000691661.1		c.3166G>A	p.Gly1056Ser	missense splice_region	Exon 27 of 35	ENSP00000510185.1	A0A8I5KYQ0

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

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

American (AMR) AF: 0.0000227 AC: 1 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: 0.00 AC: 0 AN: 1105108

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

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	-0.084	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		5.6
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.73		Gain of MoRF binding (P = 0.109)
MVP		0.60
MPC		0.62
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.92
gMVP		0.71
Mutation Taster		=22/78	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.65		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.65		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;