X-103500501-C-T

Variant names:

• chrX-103500501-C-T
• rs373230359
• NM_080879.3:c.256G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_080879.3(RAB40A):​c.256G>A​(p.Gly86Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000455 in 1,208,866 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G86V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.000047 (0 hom. 16 hem.)
• Consequence: RAB40A NM_080879.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.41
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.42230913).
• BS2: High Hemizygotes in GnomAdExome4 at 16 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080879.3. 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
	RAB40A	NM_080879.3	MANE Select	c.256G>A	p.Gly86Ser	missense	Exon 3 of 3	NP_543155.2	Q8WXH6
	LL0XNC01-250H12.3	NR_188433.1		n.2171C>T		non_coding_transcript_exon	Exon 9 of 9
	LL0XNC01-250H12.3	NR_188435.1		n.2098C>T		non_coding_transcript_exon	Exon 9 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB40A	ENST00000304236.2	TSL:2 MANE Select	c.256G>A	p.Gly86Ser	missense	Exon 3 of 3	ENSP00000305648.1	Q8WXH6
	RAB40A	ENST00000372633.1	TSL:6	c.256G>A	p.Gly86Ser	missense	Exon 1 of 1	ENSP00000361716.1	Q8WXH6
	RAB40A	ENST00000905301.1		c.256G>A	p.Gly86Ser	missense	Exon 4 of 4	ENSP00000575360.1

Frequencies

GnomAD3 genomes AF: 0.0000271 AC: 3 AN: 110800 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

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: 0.0000570

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000437 AC: 8 AN: 182949 AF XY: 0.0000297

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000613

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000474 AC: 52 AN: 1098066 Hom.: 0 Cov.: 33 AF XY: 0.0000440 AC XY: 16 AN XY: 363444

African (AFR) AF: 0.00 AC: 0 AN: 26401

American (AMR) AF: 0.0000852 AC: 3 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19364

East Asian (EAS) AF: 0.00 AC: 0 AN: 30201

South Asian (SAS) AF: 0.00 AC: 0 AN: 54127

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4132

European-Non Finnish (NFE) AF: 0.0000558 AC: 47 AN: 842030

Other (OTH) AF: 0.0000434 AC: 2 AN: 46083

GnomAD4 genome AF: 0.0000271 AC: 3 AN: 110800 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 32986

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30549

American (AMR) AF: 0.00 AC: 0 AN: 10508

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2627

East Asian (EAS) AF: 0.00 AC: 0 AN: 3521

South Asian (SAS) AF: 0.00 AC: 0 AN: 2563

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6000

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.0000570 AC: 3 AN: 52651

Other (OTH) AF: 0.00 AC: 0 AN: 1467

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00131091), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000299 AC: 2

ExAC AF: 0.0000247 AC: 3

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	0.19
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
FATHMM_MKL	Benign	0.36	N
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.42	T
MetaSVM	Uncertain	-0.066	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.4
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.063	T
Polyphen		1.0	D
Vest4		0.26
MVP		0.99
MPC		1.3
ClinPred		0.89	D
GERP RS		0.23
Varity_R		0.63
gMVP		0.82
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs373230359; hg19: chrX-102755429;