Genetic Variant NM_016024.4:c.925C>T (chrX-130412804-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

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

The NM_016024.4(RBMX2):c.925C>T(p.Arg309Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000324 in 1,208,368 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 130 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., 4 hem., cov: 21)

Exomes 𝑓: 0.00034 ( 0 hom. 126 hem. )

Consequence

RBMX2
NM_016024.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.640

Publications

1 publications found

Variant links:

Genes affected

RBMX2 (HGNC:24282): (RNA binding motif protein X-linked 2) Enables RNA binding activity. Involved in mRNA splicing, via spliceosome. Located in nucleus. Part of U2-type precatalytic spliceosome. [provided by Alliance of Genome Resources, Apr 2022]

RBMX2 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=0.020367116).

BS2

High Hemizygotes in GnomAd4 at 4 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016024.4. 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
	RBMX2	NM_016024.4	MANE Select	c.925C>T	p.Arg309Trp	missense	Exon 6 of 6	NP_057108.2	Q9Y388

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBMX2	ENST00000305536.11	TSL:1 MANE Select	c.925C>T	p.Arg309Trp	missense	Exon 6 of 6	ENSP00000339090.4	Q9Y388
	RBMX2	ENST00000919759.1		c.922C>T	p.Arg308Trp	missense	Exon 6 of 6	ENSP00000589818.1

Frequencies

GnomAD3 genomes

AF:

0.000162

AC:

AN:

111259

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000980

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000191

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000383

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000226

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000245

AC:

AN:

179649

AF XY:

0.000225

show subpopulations

Gnomad AFR exome

AF:

0.000167

Gnomad AMR exome

AF:

0.000440

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000336

Gnomad OTH exome

AF:

0.000226

GnomAD4 exome

AF:

0.000341

AC:

374

AN:

1097055

Hom.:

Cov.:

AF XY:

0.000347

AC XY:

126

AN XY:

362731

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26347

American (AMR)

AF:

0.000484

AC:

AN:

35122

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19357

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30198

South Asian (SAS)

AF:

0.000185

AC:

AN:

54004

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40513

Middle Eastern (MID)

AF:

0.000556

AC:

AN:

3595

European-Non Finnish (NFE)

AF:

0.000393

AC:

331

AN:

841907

Other (OTH)

AF:

0.000283

AC:

AN:

46012

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000153

AC:

AN:

111313

Hom.:

Cov.:

AF XY:

0.000119

AC XY:

AN XY:

33511

show subpopulations

African (AFR)

AF:

0.0000978

AC:

AN:

30671

American (AMR)

AF:

0.000190

AC:

AN:

10511

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2641

East Asian (EAS)

AF:

0.00

AC:

AN:

3509

South Asian (SAS)

AF:

0.00

AC:

AN:

2601

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5974

Middle Eastern (MID)

AF:

0.00

AC:

AN:

213

European-Non Finnish (NFE)

AF:

0.000226

AC:

AN:

52990

Other (OTH)

AF:

0.00

AC:

AN:

1520

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000304

Hom.:

Bravo

AF:

0.000204

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

ExAC

AF:

0.000290

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.94

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.16

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.75

M_CAP

Benign

0.0054

MetaRNN

Benign

0.020

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

PhyloP100

-0.64

PrimateAI

Benign

0.25

PROVEAN

Benign

-2.1

REVEL

Benign

0.013

Sift

Benign

0.085

Sift4G

Benign

0.15

Polyphen

0.0090

Vest4

0.040

MutPred

0.26

Loss of helix (P = 0.0376)

MVP

0.13

MPC

0.37

ClinPred

0.045

GERP RS

0.81

Varity_R

0.088

gMVP

0.19

Mutation Taster

=91/9

polymorphism

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over