X-120159308-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000371388.5(RHOXF2):​c.373G>A​(p.Val125Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000787 in 1,207,025 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 32 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000071 ( 0 hom., 2 hem., cov: 19)
Exomes 𝑓: 0.000079 ( 0 hom. 30 hem. )

Consequence

RHOXF2
ENST00000371388.5 missense

Scores

17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.23
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.037032515).
BS2
High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RHOXF2NM_032498.3 linkuse as main transcriptc.373G>A p.Val125Ile missense_variant 2/4 ENST00000371388.5 NP_115887.1 Q9BQY4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RHOXF2ENST00000371388.5 linkuse as main transcriptc.373G>A p.Val125Ile missense_variant 2/41 NM_032498.3 ENSP00000360441.3 Q9BQY4

Frequencies

GnomAD3 genomes
AF:
0.0000711
AC:
8
AN:
112501
Hom.:
0
Cov.:
19
AF XY:
0.0000576
AC XY:
2
AN XY:
34713
show subpopulations
Gnomad AFR
AF:
0.0000644
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000185
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000356
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000567
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000115
AC:
17
AN:
148119
Hom.:
0
AF XY:
0.000237
AC XY:
11
AN XY:
46457
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000400
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000837
Gnomad SAS exome
AF:
0.000245
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000163
Gnomad OTH exome
AF:
0.000264
GnomAD4 exome
AF:
0.0000795
AC:
87
AN:
1094479
Hom.:
0
Cov.:
31
AF XY:
0.0000832
AC XY:
30
AN XY:
360375
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000572
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000299
Gnomad4 FIN exome
AF:
0.0000249
Gnomad4 NFE exome
AF:
0.0000643
Gnomad4 OTH exome
AF:
0.000261
GnomAD4 genome
AF:
0.0000711
AC:
8
AN:
112546
Hom.:
0
Cov.:
19
AF XY:
0.0000575
AC XY:
2
AN XY:
34768
show subpopulations
Gnomad4 AFR
AF:
0.0000643
Gnomad4 AMR
AF:
0.000185
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000357
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000567
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000169
Hom.:
1
ExAC
AF:
0.000159
AC:
19

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 14, 2024The c.373G>A (p.V125I) 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 373, causing the valine (V) at amino acid position 125 to be replaced by an isoleucine (I). 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
0.085
BayesDel_addAF
Benign
-0.50
T
BayesDel_noAF
Benign
-0.66
CADD
Benign
0.031
DANN
Benign
0.87
DEOGEN2
Benign
0.0065
T
FATHMM_MKL
Benign
0.012
N
LIST_S2
Benign
0.49
T
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.037
T
MetaSVM
Benign
-0.76
T
MutationAssessor
Benign
0.69
N
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.33
T
PROVEAN
Benign
-0.22
N
REVEL
Benign
0.20
Sift
Benign
0.12
T
Sift4G
Benign
0.20
T
Polyphen
0.016
B
Vest4
0.030
MVP
0.043
MPC
1.6
ClinPred
0.026
T
GERP RS
-3.8
Varity_R
0.035
gMVP
0.22

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

LitVar

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

Other links and lift over

dbSNP: rs202000800; hg19: chrX-119293214; API