X-103499988-C-T

Variant names:

• chrX-103499988-C-T
• rs140511113
• NM_080879.3:c.769G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_080879.3(RAB40A):​c.769G>A​(p.Glu257Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0025 in 1,198,554 control chromosomes in the GnomAD database, including 19 homozygotes. There are 1,371 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0030 (3 hom., 15 hem., cov: 23)
  • Exomes 𝑓: 0.0024 (16 hom. 1356 hem.)
• Consequence: RAB40A NM_080879.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.08
• Publications: 2 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004816383).
• BS2: High Homozygotes in GnomAd4 at 3 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.769G>A	p.Glu257Lys	missense	Exon 3 of 3	NP_543155.2	Q8WXH6
	LL0XNC01-250H12.3	NR_188433.1		n.1658C>T		non_coding_transcript_exon	Exon 9 of 9
	LL0XNC01-250H12.3	NR_188435.1		n.1585C>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.769G>A	p.Glu257Lys	missense	Exon 3 of 3	ENSP00000305648.1	Q8WXH6
	RAB40A	ENST00000372633.1	TSL:6	c.769G>A	p.Glu257Lys	missense	Exon 1 of 1	ENSP00000361716.1	Q8WXH6
	RAB40A	ENST00000905301.1		c.769G>A	p.Glu257Lys	missense	Exon 4 of 4	ENSP00000575360.1

Frequencies

GnomAD3 genomes AF: 0.00301 AC: 336 AN: 111532 Hom.: 3 Cov.: 23

Gnomad AFR AF: 0.000583

Gnomad AMI AF: 0.0216

Gnomad AMR AF: 0.000846

Gnomad ASJ AF: 0.00113

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000742

Gnomad FIN AF: 0.00265

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00514

Gnomad OTH AF: 0.00197

GnomAD2 exomes AF: 0.00103 AC: 187 AN: 182192 AF XY: 0.00206

Gnomad AFR exome AF: 0.0000761

Gnomad AMR exome AF: 0.000292

Gnomad ASJ exome AF: 0.000268

Gnomad EAS exome AF: 0.0000722

Gnomad FIN exome AF: 0.000378

Gnomad NFE exome AF: 0.00194

Gnomad OTH exome AF: 0.00111

GnomAD4 exome AF: 0.00244 AC: 2657 AN: 1086969 Hom.: 16 Cov.: 33 AF XY: 0.00376 AC XY: 1356 AN XY: 361071

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

African (AFR) AF: 0.000265 AC: 7 AN: 26385

American (AMR) AF: 0.000853 AC: 30 AN: 35154

Ashkenazi Jewish (ASJ) AF: 0.00145 AC: 28 AN: 19348

East Asian (EAS) AF: 0.000166 AC: 5 AN: 30187

South Asian (SAS) AF: 0.000998 AC: 54 AN: 54103

European-Finnish (FIN) AF: 0.00372 AC: 150 AN: 40303

Middle Eastern (MID) AF: 0.00169 AC: 7 AN: 4131

European-Non Finnish (NFE) AF: 0.00270 AC: 2248 AN: 831585

Other (OTH) AF: 0.00280 AC: 128 AN: 45773

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00301 AC: 336 AN: 111585 Hom.: 3 Cov.: 23 AF XY: 0.000438 AC XY: 15 AN XY: 34233

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

African (AFR) AF: 0.000582 AC: 18 AN: 30918

American (AMR) AF: 0.000845 AC: 9 AN: 10646

Ashkenazi Jewish (ASJ) AF: 0.00113 AC: 3 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3544

South Asian (SAS) AF: 0.000744 AC: 2 AN: 2687

European-Finnish (FIN) AF: 0.00265 AC: 16 AN: 6049

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00514 AC: 271 AN: 52683

Other (OTH) AF: 0.00195 AC: 3 AN: 1539

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00443 Hom.: 54

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.00386 AC: 26

ExAC AF: 0.00391 AC: 474

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	0.065
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	2.2
DANN	Benign	0.72
DEOGEN2	Benign	0.00081	T
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.0014	T
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.7	N
PhyloP100		3.1
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.067
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.095
MVP		0.81
MPC		0.90
ClinPred		0.0070	T
GERP RS		0.23
Varity_R		0.080
gMVP		0.076
Mutation Taster		=100/0	polymorphism (auto)

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: rs140511113; hg19: chrX-102754916; COSMIC: COSV99056014;