dbSNP rs145606134: RAB40AL:p.Asp59Gly (chrX-102937494-A-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001031834.1(RAB40AL):c.176A>G(p.Asp59Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00557 in 1,210,129 control chromosomes in the GnomAD database, including 18 homozygotes. There are 2,285 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 (★).

Frequency

Genomes: 𝑓 0.0041 ( 2 hom., 150 hem., cov: 22)

Exomes 𝑓: 0.0057 ( 16 hom. 2135 hem. )

Consequence

RAB40AL
NM_001031834.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 3.12

Publications

14 publications found

Variant links:

Genes affected

RAB40AL (HGNC:25410): (RAB40A like) 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. Disruptions in this gene are associated with Duchenne muscular dystrophy. [provided by RefSeq, Apr 2010]

RAB40AL links:

LINC00630 (HGNC:44263): (long intergenic non-protein coding RNA 630)

LINC00630 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013548255).

BS2

High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB40AL	NM_001031834.1 link	c.176A>G	p.Asp59Gly	missense_variant	Exon 1 of 1	ENST00000218249.7	NP_001027004.1	P0C0E4
LINC00630	NR_146589.1 link	n.1910-21154A>G		intron_variant	Intron 10 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB40AL	ENST00000218249.7 link	c.176A>G	p.Asp59Gly	missense_variant	Exon 1 of 1	6	NM_001031834.1	ENSP00000218249.5		P0C0E4
LINC00630	ENST00000420471.6 link	n.1747+31757A>G		intron_variant	Intron 13 of 13	3

Frequencies

GnomAD3 genomes

AF:

0.00409

AC:

457

AN:

111842

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000554

Gnomad AMI

AF:

0.00293

Gnomad AMR

AF:

0.00357

Gnomad ASJ

AF:

0.0348

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00267

Gnomad FIN

AF:

0.00145

Gnomad MID

AF:

0.00418

Gnomad NFE

AF:

0.00527

Gnomad OTH

AF:

0.00732

GnomAD2 exomes

AF:

0.00539

AC:

989

AN:

183454

AF XY:

0.00575

show subpopulations

Gnomad AFR exome

AF:

0.000228

Gnomad AMR exome

AF:

0.00233

Gnomad ASJ exome

AF:

0.0348

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00156

Gnomad NFE exome

AF:

0.00635

Gnomad OTH exome

AF:

0.00729

GnomAD4 exome

AF:

0.00572

AC:

6278

AN:

1098235

Hom.:

Cov.:

AF XY:

0.00587

AC XY:

2135

AN XY:

363589

show subpopulations

African (AFR)

AF:

0.000871

AC:

AN:

26403

American (AMR)

AF:

0.00207

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.0340

AC:

659

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30204

South Asian (SAS)

AF:

0.00375

AC:

203

AN:

54146

European-Finnish (FIN)

AF:

0.00192

AC:

AN:

40533

Middle Eastern (MID)

AF:

0.0116

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.00583

AC:

4909

AN:

842128

Other (OTH)

AF:

0.00618

AC:

285

AN:

46094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

316

631

947

1262

1578

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00408

AC:

457

AN:

111894

Hom.:

Cov.:

AF XY:

0.00440

AC XY:

150

AN XY:

34076

show subpopulations

African (AFR)

AF:

0.000553

AC:

AN:

30733

American (AMR)

AF:

0.00356

AC:

AN:

10662

Ashkenazi Jewish (ASJ)

AF:

0.0348

AC:

AN:

2646

East Asian (EAS)

AF:

0.00

AC:

AN:

3521

South Asian (SAS)

AF:

0.00268

AC:

AN:

2610

European-Finnish (FIN)

AF:

0.00145

AC:

AN:

6193

Middle Eastern (MID)

AF:

0.00459

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00527

AC:

280

AN:

53106

Other (OTH)

AF:

0.00723

AC:

AN:

1522

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

102

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00588

Hom.:

Bravo

AF:

0.00404

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.00479

AC:

581

EpiCase

AF:

0.00665

EpiControl

AF:

0.00777

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Deafness-intellectual disability, Martin-Probst type syndrome

Uncertain:1

Oct 01, 2014

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Uncertain:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

FATHMM_MKL

Benign

0.68

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.0092

MetaRNN

Benign

0.014

MetaSVM

Uncertain

-0.12

MutationAssessor

Benign

1.2

PhyloP100

3.1

PrimateAI

Benign

0.40

PROVEAN

Pathogenic

-6.0

REVEL

Uncertain

0.55

Sift

Pathogenic

0.0

Sift4G

Benign

0.16

Polyphen

1.0

Vest4

0.11

MVP

0.95

MPC

1.4

ClinPred

0.053

GERP RS

0.78

PromoterAI

0.018

Neutral

(source)

Varity_R

0.87

gMVP

0.82

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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rs145606134

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over