chrX-120159425-C-G

Variant names:

• chrX-120159425-C-G
• rs782713247
• NM_032498.3:c.490C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_032498.3(RHOXF2):​c.490C>G​(p.Arg164Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 19)
• Consequence: RHOXF2 NM_032498.3 missense, splice_region
• Scores: Splicing: ADA: 0.0001006
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.23
• Publications: 0 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_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976

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.490C>G	p.Arg164Gly	missense splice_region	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.490C>G	p.Arg164Gly	missense splice_region	Exon 2 of 4	ENSP00000360441.3	Q9BQY4
	RHOXF1	ENST00000703667.1		c.-628-22236G>C		intron	N/A	ENSP00000515423.1	Q8NHV9
	RHOXF1	ENST00000555168.1	TSL:4	n.126-22236G>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 19

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 19

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	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	12
DANN	Benign	0.88
DEOGEN2	Pathogenic	0.89	D
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0042	T
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		-1.2
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.019	D
Polyphen		1.0	D
Vest4		0.55
MutPred		0.95		Loss of MoRF binding (P = 0.0259)
MVP		0.78
MPC		3.3
ClinPred		0.64	D
GERP RS		-4.1
Varity_R		0.52
gMVP		0.37
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00010
dbscSNV1_RF	Benign	0.11
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.30		Position offset: -12

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

Other links and lift over

dbSNP: rs782713247; hg19: chrX-119293331;