9-122986408-A-C

Variant names:

• chr9-122986408-A-C
• NM_012197.4:c.579A>C

Variant summary

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

The NM_012197.4(RABGAP1):​c.579A>C​(p.Glu193Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RABGAP1 NM_012197.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.04
• Publications: 0 publications found

Genes affected

RABGAP1 (HGNC:17155): (RAB GTPase activating protein 1) Enables GTPase activator activity and small GTPase binding activity. Involved in regulation of GTPase activity. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

RABGAP1 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: MODERATE Submitted by: G2P

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=0.41018963).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012197.4. 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
	RABGAP1	NM_012197.4	MANE Select	c.579A>C	p.Glu193Asp	missense	Exon 4 of 26	NP_036329.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RABGAP1	ENST00000373647.9	TSL:1 MANE Select	c.579A>C	p.Glu193Asp	missense	Exon 4 of 26	ENSP00000362751.4	Q9Y3P9-1
	RABGAP1	ENST00000870248.1		c.579A>C	p.Glu193Asp	missense	Exon 4 of 27	ENSP00000540307.1
	RABGAP1	ENST00000941860.1		c.579A>C	p.Glu193Asp	missense	Exon 4 of 27	ENSP00000611919.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.0044	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.32	N
PhyloP100		1.0
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.28
Sift	Benign	0.33	T
Sift4G	Benign	0.56	T
Polyphen		0.0030	B
Vest4		0.66
MutPred		0.73		Gain of sheet (P = 0.0149)
MVP		0.57
MPC		0.98
ClinPred		0.31	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.50
Mutation Taster		=84/16	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

hg19: chr9-125748687;