Genetic Variant RHOXF2B:p.Gly84Arg (chrX-120077118-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_001099685.3(RHOXF2B):c.250G>A(p.Gly84Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000609 in 1,050,523 control chromosomes in the GnomAD database, including 8 homozygotes. There are 14 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 0.00016 ( 1 hom., 0 hem., cov: 14)

Exomes 𝑓: 0.000052 ( 7 hom. 14 hem. )

Consequence

RHOXF2B
NM_001099685.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.184

Publications

2 publications found

Variant links:

Genes affected

RHOXF2B (HGNC:33519): (Rhox homeobox family member 2B) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Involved in positive regulation of gene expression. Predicted to be located in nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

RHOXF2B links:

RHOXF1-AS1 (HGNC:51582): (RHOXF1 antisense RNA 1)

RHOXF1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.053393513).

BS2

High Homozygotes in GnomAdExome4 at 7 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001099685.3. 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
	RHOXF2B	NM_001099685.3	MANE Select	c.250G>A	p.Gly84Arg	missense	Exon 2 of 4	NP_001093155.1	P0C7M4
	RHOXF1-AS1	NR_131238.1		n.297+40586C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHOXF2B	ENST00000371402.5	TSL:1 MANE Select	c.250G>A	p.Gly84Arg	missense	Exon 2 of 4	ENSP00000360455.3	P0C7M4
	RHOXF1-AS1	ENST00000553843.5	TSL:2	n.297+40586C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000163

AC:

AN:

86146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000310

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000277

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:

0.0000904

Gnomad OTH

AF:

0.000911

GnomAD2 exomes

AF:

0.000118

AC:

AN:

152274

AF XY:

0.0000616

show subpopulations

Gnomad AFR exome

AF:

0.000808

Gnomad AMR exome

AF:

0.000227

Gnomad ASJ exome

AF:

0.000470

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000142

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000518

AC:

AN:

964377

Hom.:

Cov.:

AF XY:

0.0000509

AC XY:

AN XY:

275285

show subpopulations

African (AFR)

AF:

0.000392

AC:

AN:

22964

American (AMR)

AF:

0.000176

AC:

AN:

28405

Ashkenazi Jewish (ASJ)

AF:

0.000300

AC:

AN:

16679

East Asian (EAS)

AF:

0.00

AC:

AN:

21713

South Asian (SAS)

AF:

0.0000520

AC:

AN:

38480

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38262

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3694

European-Non Finnish (NFE)

AF:

0.0000305

AC:

AN:

753869

Other (OTH)

AF:

0.000149

AC:

AN:

40311

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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

<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:

0.000163

AC:

AN:

86146

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

20342

show subpopulations

African (AFR)

AF:

0.000310

AC:

AN:

22591

American (AMR)

AF:

0.000277

AC:

AN:

7220

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2085

East Asian (EAS)

AF:

0.00

AC:

AN:

2212

South Asian (SAS)

AF:

0.00

AC:

AN:

1424

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4548

Middle Eastern (MID)

AF:

0.00

AC:

AN:

183

European-Non Finnish (NFE)

AF:

0.0000904

AC:

AN:

44228

Other (OTH)

AF:

0.000911

AC:

AN:

1098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.417

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0000458

Hom.:

ESP6500AA

AF:

0.000569

AC:

ESP6500EA

AF:

0.000324

AC:

ExAC

AF:

0.000157

AC:

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

0.14

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.014

FATHMM_MKL

Benign

0.0032

LIST_S2

Benign

0.32

M_CAP

Benign

0.011

MetaRNN

Benign

0.053

MetaSVM

Benign

-0.31

MutationAssessor

Benign

0.97

PhyloP100

-0.18

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.27

REVEL

Benign

0.28

Sift

Uncertain

0.020

Sift4G

Uncertain

0.018

Polyphen

0.97

Vest4

0.097

MutPred

0.38

Gain of solvent accessibility (P = 0.0055)

MVP

0.043

MPC

2.7

ClinPred

0.024

GERP RS

-0.20

Varity_R

0.11

gMVP

0.083

Mutation Taster

=100/0

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