X-120076950-C-G

Variant names:

• chrX-120076950-C-G
• rs1555996233
• NM_001099685.3:c.418G>C

Variant summary

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

The NM_001099685.3(RHOXF2B):​c.418G>C​(p.Ala140Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 8)
  • Exomes 𝑓: 0.000013 (0 hom. 7 hem.)
  • Failed GnomAD Quality Control
• Consequence: RHOXF2B NM_001099685.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -4.52

Genes affected

RHOXF2B (HGNC:33519): (Rhox homeobox family member 2B) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Involved in positive regulation of gene expression. Predicted to be located in nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

RHOXF1-AS1 (HGNC:51582): (RHOXF1 antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15069875).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHOXF2B	NM_001099685.3	c.418G>C	p.Ala140Pro	missense_variant	Exon 2 of 4	ENST00000371402.5	NP_001093155.1
RHOXF1-AS1	NR_131238.1	n.297+40418C>G		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHOXF2B	ENST00000371402.5	c.418G>C	p.Ala140Pro	missense_variant	Exon 2 of 4	1	NM_001099685.3	ENSP00000360455.3
RHOXF1-AS1	ENST00000553843.5	n.297+40418C>G		intron_variant	Intron 1 of 4	2

Frequencies

GnomAD3 genomes Cov.: 8

GnomAD3 exomes AF: 0.00000934 AC: 1 AN: 107082 Hom.: 0 AF XY: 0.0000342 AC XY: 1 AN XY: 29212

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000575

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: 0.0000134 AC: 10 AN: 748345 Hom.: 0 Cov.: 26 AF XY: 0.0000357 AC XY: 7 AN XY: 196307

Gnomad4 AFR exome AF: 0.0000588

Gnomad4 AMR exome AF: 0.0000868

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: 0.0000120

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.418G>C (p.A140P) alteration is located in exon 2 (coding exon 2) of the RHOXF2B gene. This alteration results from a G to C substitution at nucleotide position 418, causing the alanine (A) at amino acid position 140 to be replaced by a proline (P). 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	0.19
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	0.0040
DANN	Benign	0.37
DEOGEN2	Benign	0.032	T
FATHMM_MKL	Benign	0.00052	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	0.46	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.32
Sift	Benign	0.18	T
Sift4G	Benign	0.32	T
Polyphen		0.014	B
Vest4		0.19
MutPred		0.53		Gain of disorder (P = 0.0455);
MVP		0.043
MPC		2.3
ClinPred		0.095	T
GERP RS		-1.9
Varity_R		0.13
gMVP		0.14

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

Other links and lift over

dbSNP: rs1555996233; hg19: chrX-119210915;