NM_012414.4:c.1511T>C

Variant names:

• chr1-220190497-A-G
• rs1553276414
• NM_012414.4:c.1511T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012414.4(RAB3GAP2):​c.1511T>C​(p.Ile504Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: RAB3GAP2 NM_012414.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.85
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40127563).

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.1511T>C	p.Ile504Thr	missense	Exon 15 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.1511T>C	p.Ile504Thr	missense	Exon 15 of 35	ENSP00000351832.2	Q9H2M9-1
	RAB3GAP2	ENST00000692972.1		c.1586T>C	p.Ile529Thr	missense	Exon 16 of 36	ENSP00000510753.1	A0A8I5KZB3
	RAB3GAP2	ENST00000691661.1		c.1523T>C	p.Ile508Thr	missense	Exon 15 of 35	ENSP00000510185.1	A0A8I5KYQ0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Martsolf syndrome;C3280214:Warburg micro syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.055	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		8.8
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.26
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.33	B
Vest4		0.68
MutPred		0.36		Loss of stability (P = 0.0346)
MVP		0.14
MPC		0.29
ClinPred		0.86	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.44
Mutation Taster		=63/37	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: rs1553276414; hg19: chr1-220363839;