2-135130711-C-T

Variant names:

• chr2-135130711-C-T
• rs149010855
• NM_012233.3:c.1226C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS1

The NM_012233.3(RAB3GAP1):​c.1226C>T​(p.Thr409Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000558 in 1,612,414 control chromosomes in the GnomAD database, including 1 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00030 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: RAB3GAP1 NM_012233.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 7.24
• Publications: 0 publications found

Genes affected

RAB3GAP1 (HGNC:17063): (RAB3 GTPase activating protein catalytic subunit 1) This gene encodes the catalytic subunit of a Rab GTPase activating protein. The encoded protein forms a heterodimer with a non-catalytic subunit to specifically regulate the activity of members of the Rab3 subfamily of small G proteins. This protein mediates the hydrolysis of GTP bound Rab3 to the GDP bound form. Mutations in this gene are associated with Warburg micro syndrome. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Feb 2010]

RAB3GAP1 Gene-Disease associations (from GenCC):

• Warburg micro syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Warburg micro syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• cataract-intellectual disability-hypogonadism syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.050635487).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000295 (45/152322) while in subpopulation AFR AF = 0.00108 (45/41580). AF 95% confidence interval is 0.000831. There are 1 homozygotes in GnomAd4. There are 19 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012233.3. 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
	RAB3GAP1	NM_012233.3	MANE Select	c.1226C>T	p.Thr409Ile	missense	Exon 13 of 24	NP_036365.1	B9A6J2
	RAB3GAP1	NM_001172435.2		c.1226C>T	p.Thr409Ile	missense	Exon 13 of 25	NP_001165906.1	Q15042-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB3GAP1	ENST00000264158.13	TSL:1 MANE Select	c.1226C>T	p.Thr409Ile	missense	Exon 13 of 24	ENSP00000264158.8	Q15042-1
	RAB3GAP1	ENST00000442034.5	TSL:1	c.1226C>T	p.Thr409Ile	missense	Exon 13 of 25	ENSP00000411418.1	Q15042-3
	RAB3GAP1	ENST00000970735.1		c.1229C>T	p.Thr410Ile	missense	Exon 13 of 24	ENSP00000640794.1

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152204 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000956 AC: 24 AN: 250982 AF XY: 0.0000442

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000308 AC: 45 AN: 1460092 Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18 AN XY: 726450

African (AFR) AF: 0.00129 AC: 43 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110548

Other (OTH) AF: 0.0000331 AC: 2 AN: 60338

GnomAD4 genome AF: 0.000295 AC: 45 AN: 152322 Hom.: 1 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74478

African (AFR) AF: 0.00108 AC: 45 AN: 41580

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.000340

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000140 AC: 17

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	1	-	Inborn genetic diseases (1)
-	1	-	Warburg micro syndrome 1;C5543626:Martsolf syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Benign	0.10
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.0	L
PhyloP100		7.2
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.063
Sift	Benign	0.056	T
Sift4G	Benign	0.17	T
Polyphen		0.047	B
Vest4		0.56
MVP		0.74
MPC		0.25
ClinPred		0.14	T
GERP RS		5.3
Varity_R		0.12
gMVP		0.31
Mutation Taster		=64/36	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs149010855; hg19: chr2-135888281;