X-13708832-C-T

Position:

• chrX-13708832-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000464506.2(RAB9A):​c.86C>T​(p.Thr29Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000183 in 1,094,913 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: RAB9A ENST00000464506.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.93

Genes affected

RAB9A (HGNC:9792): (RAB9A, member RAS oncogene family) Enables GDP binding activity; GTP binding activity; and GTPase activity. Involved in negative regulation by host of symbiont catalytic activity; positive regulation of exocytosis; and regulation of protein localization. Located in late endosome; lysosome; and phagocytic vesicle. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAB9A	NM_004251.5	c.86C>T	p.Thr29Ile	missense_variant	3/3	ENST00000464506.2	NP_004242.1
RAB9A	NM_001195328.2	c.86C>T	p.Thr29Ile	missense_variant	2/2		NP_001182257.1
RAB9A	XM_047442644.1	c.86C>T	p.Thr29Ile	missense_variant	3/3		XP_047298600.1
RAB9A	XM_047442645.1	c.86C>T	p.Thr29Ile	missense_variant	3/3		XP_047298601.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAB9A	ENST00000464506.2	c.86C>T	p.Thr29Ile	missense_variant	3/3	1	NM_004251.5	ENSP00000420127.1
RAB9A	ENST00000618931.2	c.86C>T	p.Thr29Ile	missense_variant	2/2	2		ENSP00000480777.1
RAB9A	ENST00000243325.6	c.*15C>T		downstream_gene_variant		3		ENSP00000490117.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1094913 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 360525

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000238

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

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

Jan 10, 2022

The c.86C>T (p.T29I) alteration is located in exon 3 (coding exon 1) of the RAB9A gene. This alteration results from a C to T substitution at nucleotide position 86, causing the threonine (T) at amino acid position 29 to be replaced by an isoleucine (I). 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	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;D
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.92	.;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.2	D;.
REVEL	Uncertain	0.59
Sift	Uncertain	0.0030	D;.
Sift4G	Uncertain	0.018	D;D
Polyphen		0.89	P;P
Vest4		0.69
MutPred		0.46		Loss of ubiquitination at K31 (P = 0.0982);Loss of ubiquitination at K31 (P = 0.0982);
MVP		0.94
MPC		1.9
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.75
gMVP		0.86

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-13726951;