9-122986397-A-T

Position:

• chr9-122986397-A-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

The NM_012197.4(RABGAP1):​c.568A>T​(p.Asn190Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,802 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: RABGAP1 NM_012197.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.93

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RABGAP1
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RABGAP1	NM_012197.4	c.568A>T	p.Asn190Tyr	missense_variant	4/26	ENST00000373647.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RABGAP1	ENST00000373647.9	c.568A>T	p.Asn190Tyr	missense_variant	4/26	1	NM_012197.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251236 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135772

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461802 Hom.: 0 Cov.: 30 AF XY: 0.00000963 AC XY: 7 AN XY: 727208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2021

The c.568A>T (p.N190Y) alteration is located in exon 4 (coding exon 3) of the RABGAP1 gene. This alteration results from a A to T substitution at nucleotide position 568, causing the asparagine (N) at amino acid position 190 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.057	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.047	D
Polyphen		0.92	P
Vest4		0.67
MutPred		0.41		Loss of solvent accessibility (P = 0.0193);
MVP		0.32
MPC		1.1
ClinPred		0.77	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1355164752; hg19: chr9-125748676;