Genetic Variant RHOXF2:p.Leu146Val (chrX-120159371-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_032498.3(RHOXF2):c.436C>G(p.Leu146Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000070 ( 0 hom., 0 hem., cov: 19)

Exomes 𝑓: 0.000014 ( 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: -1.49

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 made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14005908).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHOXF2	NM_032498.3 link	c.436C>G	p.Leu146Val	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.436C>G	p.Leu146Val	missense_variant	Exon 2 of 4	1	NM_032498.3	ENSP00000360441.3		Q9BQY4

Frequencies

GnomAD3 genomes

AF:

0.0000705

AC:

AN:

113451

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35573

show subpopulations

Gnomad AFR

AF:

0.000256

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000167

AC:

AN:

180073

Hom.:

AF XY:

0.00

AC XY:

AN XY:

66111

show subpopulations

Gnomad AFR exome

AF:

0.000230

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000137

AC:

AN:

1096381

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

361911

show subpopulations

Gnomad4 AFR exome

AF:

0.000266

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000476

Gnomad4 OTH exome

AF:

0.0000869

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000705

AC:

AN:

113503

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35635

show subpopulations

Gnomad4 AFR

AF:

0.000255

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000960

Hom.:

ExAC

AF:

0.0000495

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.436C>G (p.L146V) alteration is located in exon 2 (coding exon 2) of the RHOXF2 gene. This alteration results from a C to G substitution at nucleotide position 436, causing the leucine (L) at amino acid position 146 to be replaced by a valine (V). 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

0.14

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.26

CADD

Benign

0.15

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.67

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.76

M_CAP

Benign

0.0067

MetaRNN

Benign

0.14

MetaSVM

Uncertain

0.16

MutationAssessor

Benign

1.4

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-2.4

REVEL

Uncertain

0.35

Sift

Uncertain

0.0080

Sift4G

Benign

0.13

Polyphen

0.56

Vest4

0.17

MutPred

0.69

Gain of catalytic residue at L146 (P = 0.071);

MVP

0.12

MPC

2.1

ClinPred

0.080

GERP RS

-3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.12

gMVP

0.092

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over