X-120077148-C-T

Variant names:

• chrX-120077148-C-T
• rs782290026
• NM_001099685.3:c.220G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001099685.3(RHOXF2B):​c.220G>A​(p.Gly74Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000974 in 964,819 control chromosomes in the GnomAD database, including 14 homozygotes. There are 26 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., 1 hem., cov: 13)
  • Exomes 𝑓: 0.000097 (14 hom. 26 hem.)
  • Failed GnomAD Quality Control
• Consequence: RHOXF2B NM_001099685.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.849
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13832551).
• BS2: High Homozygotes in GnomAdExome4 at 14 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001099685.3. 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
	RHOXF2B	NM_001099685.3	MANE Select	c.220G>A	p.Gly74Ser	missense	Exon 2 of 4	NP_001093155.1	P0C7M4
	RHOXF1-AS1	NR_131238.1		n.297+40616C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHOXF2B	ENST00000371402.5	TSL:1 MANE Select	c.220G>A	p.Gly74Ser	missense	Exon 2 of 4	ENSP00000360455.3	P0C7M4
	RHOXF1-AS1	ENST00000553843.5	TSL:2	n.297+40616C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000113 AC: 9 AN: 79573 Hom.: 0 Cov.: 13

Gnomad AFR AF: 0.000193

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: 0.000120

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000101 AC: 15 AN: 149218 AF XY: 0.0000835

Gnomad AFR exome AF: 0.0000977

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: 0.000189

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000974 AC: 94 AN: 964819 Hom.: 14 Cov.: 30 AF XY: 0.0000943 AC XY: 26 AN XY: 275605

African (AFR) AF: 0.0000435 AC: 1 AN: 22996

American (AMR) AF: 0.0000352 AC: 1 AN: 28398

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16732

East Asian (EAS) AF: 0.00 AC: 0 AN: 21748

South Asian (SAS) AF: 0.0000520 AC: 2 AN: 38469

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38257

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3687

European-Non Finnish (NFE) AF: 0.000118 AC: 89 AN: 754208

Other (OTH) AF: 0.0000248 AC: 1 AN: 40324

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000113 AC: 9 AN: 79591 Hom.: 0 Cov.: 13 AF XY: 0.0000577 AC XY: 1 AN XY: 17323

African (AFR) AF: 0.000193 AC: 4 AN: 20727

American (AMR) AF: 0.00 AC: 0 AN: 6518

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1951

East Asian (EAS) AF: 0.00 AC: 0 AN: 1997

South Asian (SAS) AF: 0.00 AC: 0 AN: 1235

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3981

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 155

European-Non Finnish (NFE) AF: 0.000121 AC: 5 AN: 41486

Other (OTH) AF: 0.00 AC: 0 AN: 1015

Alfa AF: 0.0000510 Hom.: 0

ExAC AF: 0.000101 AC: 10

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	0.084
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	0.13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0089	T
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.14	T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	0.90	L
PhyloP100		-0.85
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.57	N
REVEL	Benign	0.24
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.045	D
Polyphen		1.0	D
Vest4		0.13
MVP		0.12
MPC		2.8
ClinPred		0.055	T
GERP RS		0.88
Varity_R		0.090
gMVP		0.069
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs782290026; hg19: chrX-119211113; COSMIC: COSV65054934;