X-68212097-T-G

Variant names:

• chrX-68212097-T-G
• rs375325266
• NM_002547.3:c.702+11A>C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_002547.3(OPHN1):​c.702+11A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,139,718 control chromosomes in the GnomAD database, including 3 homozygotes. There are 587 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., 33 hem., cov: 23)
  • Exomes 𝑓: 0.0019 (3 hom. 554 hem.)
• Consequence: OPHN1 NM_002547.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.0500

Genes affected

OPHN1 (HGNC:8148): (oligophrenin 1) This gene encodes a Rho-GTPase-activating protein that promotes GTP hydrolysis of Rho subfamily members. Rho proteins are important mediators of intracellular signal transduction, which affects cell migration and cell morphogenesis. Mutations in this gene are responsible for OPHN1-related X-linked cognitive disability with cerebellar hypoplasia and distinctive facial dysmorhphism. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant X-68212097-T-G is Benign according to our data. Variant chrX-68212097-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 159478.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}. Variant chrX-68212097-T-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00117 (131/111938) while in subpopulation AMR AF= 0.00218 (23/10547). AF 95% confidence interval is 0.00149. There are 0 homozygotes in gnomad4. There are 33 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 33 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPHN1	NM_002547.3	c.702+11A>C		intron_variant	Intron 8 of 24	ENST00000355520.6	NP_002538.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPHN1	ENST00000355520.6	c.702+11A>C		intron_variant	Intron 8 of 24	1	NM_002547.3	ENSP00000347710.5

Frequencies

GnomAD3 genomes AF: 0.00117 AC: 131 AN: 111938 Hom.: 0 Cov.: 23 AF XY: 0.000967 AC XY: 33 AN XY: 34128

Gnomad AFR AF: 0.000422

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00218

Gnomad ASJ AF: 0.00226

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000164

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00166

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00130 AC: 213 AN: 163335 Hom.: 0 AF XY: 0.00112 AC XY: 58 AN XY: 51569

Gnomad AFR exome AF: 0.000937

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00183

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000243

Gnomad FIN exome AF: 0.000136

Gnomad NFE exome AF: 0.00191

Gnomad OTH exome AF: 0.00170

GnomAD4 exome AF: 0.00185 AC: 1902 AN: 1027780 Hom.: 3 Cov.: 20 AF XY: 0.00179 AC XY: 554 AN XY: 309376

Gnomad4 AFR exome AF: 0.000280

Gnomad4 AMR exome AF: 0.00161

Gnomad4 ASJ exome AF: 0.00192

Gnomad4 EAS exome AF: 0.0000336

Gnomad4 SAS exome AF: 0.000430

Gnomad4 FIN exome AF: 0.000100

Gnomad4 NFE exome AF: 0.00215

Gnomad4 OTH exome AF: 0.00208

GnomAD4 genome AF: 0.00117 AC: 131 AN: 111938 Hom.: 0 Cov.: 23 AF XY: 0.000967 AC XY: 33 AN XY: 34128

Gnomad4 AFR AF: 0.000422

Gnomad4 AMR AF: 0.00218

Gnomad4 ASJ AF: 0.00226

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000164

Gnomad4 NFE AF: 0.00166

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00105 Hom.: 5

Bravo AF: 0.00139

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

X-linked intellectual disability-cerebellar hypoplasia syndrome Uncertain:1

Jun 12, 2013

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Oct 18, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.0
DANN	Benign	0.56

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: rs375325266; hg19: chrX-67431939;