NM_032498.3:c.436C>G

Variant names:

• chrX-120159371-C-G
• rs782288176
• NM_032498.3:c.436C>G

Variant summary

Our verdict is Likely benign. The variant received -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. 12/21 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.49
• Publications: 2 publications found

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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.14005908).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032498.3. 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
	RHOXF2	NM_032498.3	MANE Select	c.436C>G	p.Leu146Val	missense	Exon 2 of 4	NP_115887.1	Q9BQY4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHOXF2	ENST00000371388.5	TSL:1 MANE Select	c.436C>G	p.Leu146Val	missense	Exon 2 of 4	ENSP00000360441.3	Q9BQY4
	RHOXF1	ENST00000703667.1		c.-628-22182G>C		intron	N/A	ENSP00000515423.1	Q8NHV9
	RHOXF1	ENST00000555168.1	TSL:4	n.126-22182G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000705 AC: 8 AN: 113451 Hom.: 0 Cov.: 19

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

GnomAD2 exomes AF: 0.0000167 AC: 3 AN: 180073 AF XY: 0.00

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 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: 15 AN: 1096381 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 361911

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

African (AFR) AF: 0.000266 AC: 7 AN: 26359

American (AMR) AF: 0.00 AC: 0 AN: 35162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19381

East Asian (EAS) AF: 0.00 AC: 0 AN: 30159

South Asian (SAS) AF: 0.00 AC: 0 AN: 53939

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40481

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4030

European-Non Finnish (NFE) AF: 0.00000476 AC: 4 AN: 840857

Other (OTH) AF: 0.0000869 AC: 4 AN: 46013

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000705 AC: 8 AN: 113503 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 35635

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

African (AFR) AF: 0.000255 AC: 8 AN: 31351

American (AMR) AF: 0.00 AC: 0 AN: 10864

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2664

East Asian (EAS) AF: 0.00 AC: 0 AN: 3647

South Asian (SAS) AF: 0.00 AC: 0 AN: 2875

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6313

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53338

Other (OTH) AF: 0.00 AC: 0 AN: 1546

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000588567), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000960 Hom.: 0

ExAC AF: 0.0000495 AC: 6

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	0.15
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.14	T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.4	L
PhyloP100		-1.5
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.13	T
Polyphen		0.56	P
Vest4		0.17
MutPred		0.69		Gain of catalytic residue at L146 (P = 0.071)
MVP		0.12
MPC		2.1
ClinPred		0.080	T
GERP RS		-3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.092
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs782288176; hg19: chrX-119293277;