X-103500389-A-C

Variant names:

• chrX-103500389-A-C
• NM_080879.3:c.368T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_080879.3(RAB40A):​c.368T>G​(p.Leu123Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: RAB40A NM_080879.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.52

Genes affected

RAB40A (HGNC:18283): (RAB40A, member RAS oncogene family) This gene encodes a member of the Rab40 subfamily of Rab small GTP-binding proteins that contains a C-terminal suppressors of cytokine signaling box. [provided by RefSeq, Apr 2010]

LL0XNC01-250H12.3 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB40A	NM_080879.3	c.368T>G	p.Leu123Arg	missense_variant	Exon 3 of 3	ENST00000304236.2	NP_543155.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB40A	ENST00000304236.2	c.368T>G	p.Leu123Arg	missense_variant	Exon 3 of 3	2	NM_080879.3	ENSP00000305648.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.368T>G (p.L123R) alteration is located in exon 3 (coding exon 1) of the RAB40A gene. This alteration results from a T to G substitution at nucleotide position 368, causing the leucine (L) at amino acid position 123 to be replaced by an arginine (R). 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	0.88
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;D
FATHMM_MKL	Benign	0.74	D
LIST_S2	Pathogenic	1.0	.;D
M_CAP	Benign	0.0030	T
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Pathogenic	3.6	H;H
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.88
MutPred		0.86		Gain of MoRF binding (P = 0.0075);Gain of MoRF binding (P = 0.0075);
MVP		0.93
MPC		2.3
ClinPred		1.0	D
GERP RS		0.23
Varity_R		0.98
gMVP		0.96

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-102755317;