Genetic Variant RHOXF2:p.Ala133Thr (chrX-120159332-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_032498.3(RHOXF2):c.397G>A(p.Ala133Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A133G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 19)

Exomes 𝑓: 0.0000036 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

RHOXF2
NM_032498.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.668

Publications

0 publications found

Variant links:

Genes affected

RHOXF2 (HGNC:30011): (Rhox homeobox family member 2) This gene, which encodes a transcriptional repressor, is one of two paralogous X-linked homeobox-containing genes and is highly expressed in a variety of cancers. In addition, the encoded protein associates with the cell membrane and with microtubules, and is concentrated at the leading edge of migratory cells. [provided by RefSeq, Dec 2015]

RHOXF2 links:

RHOXF1 (HGNC:29993): (Rhox homeobox family member 1) This gene is a member of the PEPP subfamily of paired-like homoebox genes. The gene may be regulated by androgens and epigenetic mechanisms. The encoded nuclear protein is likely a transcription factor that may play a role in human reproduction. [provided by RefSeq, Dec 2012]

RHOXF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08146694).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHOXF2	NM_032498.3 link	c.397G>A	p.Ala133Thr	missense_variant	Exon 2 of 4	ENST00000371388.5	NP_115887.1	Q9BQY4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHOXF2	ENST00000371388.5 link	c.397G>A	p.Ala133Thr	missense_variant	Exon 2 of 4	1	NM_032498.3	ENSP00000360441.3		Q9BQY4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000580

AC:

AN:

172554

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000133

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000365

AC:

AN:

1096119

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

361749

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

26351

American (AMR)

AF:

0.00

AC:

AN:

35094

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19352

East Asian (EAS)

AF:

0.00

AC:

AN:

30144

South Asian (SAS)

AF:

0.00

AC:

AN:

53874

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40374

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3991

European-Non Finnish (NFE)

AF:

0.00000476

AC:

AN:

840952

Other (OTH)

AF:

0.00

AC:

AN:

45987

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000005), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000509

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 06, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.397G>A (p.A133T) alteration is located in exon 2 (coding exon 2) of the RHOXF2 gene. This alteration results from a G to A substitution at nucleotide position 397, causing the alanine (A) at amino acid position 133 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

CADD

Benign

0.24

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.011

FATHMM_MKL

Benign

0.0066

LIST_S2

Benign

0.51

M_CAP

Benign

0.0075

MetaRNN

Benign

0.081

MetaSVM

Benign

-0.49

MutationAssessor

Benign

0.81

PhyloP100

-0.67

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.30

REVEL

Benign

0.28

Sift

Benign

0.17

Sift4G

Benign

0.58

Polyphen

0.75

Vest4

0.071

MutPred

0.16

Gain of glycosylation at A133 (P = 0.0039);

MVP

0.12

MPC

2.5

ClinPred

0.089

GERP RS

-4.2

Varity_R

0.030

gMVP

0.086

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over