rs369382527

Variant names:

• chrX-68212100-A-C
• rs369382527
• NM_002547.3:c.702+8T>G

Your query was ambiguous. Multiple possible variants found:

• chrX-68212100-A-C
• chrX-68212100-A-G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS2_Supporting

The NM_002547.3(OPHN1):​c.702+8T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000348 in 1,150,548 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 9.6e-7 (0 hom. 1 hem.)
• Consequence: OPHN1 NM_002547.3 splice_region, intron
• Scores: Splicing: ADA: 0.001022
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.11
• Publications: 0 publications found

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]

OPHN1 Gene-Disease associations (from GenCC):

• X-linked intellectual disability-cerebellar hypoplasia syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BS2: High Hemizygotes in GnomAd4 at 2 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPHN1	NM_002547.3	c.702+8T>G		splice_region_variant, 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+8T>G		splice_region_variant, intron_variant	Intron 8 of 24	1	NM_002547.3	ENSP00000347710.5

Frequencies

GnomAD3 genomes AF: 0.0000268 AC: 3 AN: 112070 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000973

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

GnomAD4 exome AF: 9.63e-7 AC: 1 AN: 1038478 Hom.: 0 Cov.: 21 AF XY: 0.00000316 AC XY: 1 AN XY: 316734

African (AFR) AF: 0.0000396 AC: 1 AN: 25240

American (AMR) AF: 0.00 AC: 0 AN: 34416

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18867

East Asian (EAS) AF: 0.00 AC: 0 AN: 29829

South Asian (SAS) AF: 0.00 AC: 0 AN: 51444

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40101

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3990

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 790434

Other (OTH) AF: 0.00 AC: 0 AN: 44157

GnomAD4 genome AF: 0.0000268 AC: 3 AN: 112070 Hom.: 0 Cov.: 23 AF XY: 0.0000584 AC XY: 2 AN XY: 34224

African (AFR) AF: 0.0000973 AC: 3 AN: 30832

American (AMR) AF: 0.00 AC: 0 AN: 10559

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3582

South Asian (SAS) AF: 0.00 AC: 0 AN: 2692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6087

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53230

Other (OTH) AF: 0.00 AC: 0 AN: 1509

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	10
DANN	Benign	0.63
PhyloP100		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0010
dbscSNV1_RF	Benign	0.022
SpliceAI score (max)		0.010		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: rs369382527; hg19: chrX-67431942;