X-68053635-C-A

Variant names:

• chrX-68053635-C-A
• rs144475530
• NM_002547.3:c.2324+10G>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_002547.3(OPHN1):​c.2324+10G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000476 in 1,208,632 control chromosomes in the GnomAD database, including 1 homozygotes. There are 159 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., 77 hem., cov: 22)
  • Exomes 𝑓: 0.00028 (0 hom. 82 hem.)
• Consequence: OPHN1 NM_002547.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.515
• 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: ClinGen, G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant X-68053635-C-A is Benign according to our data. Variant chrX-68053635-C-A is described in ClinVar as Benign. ClinVar VariationId is 195675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00239 (267/111804) while in subpopulation AFR AF = 0.00786 (242/30803). AF 95% confidence interval is 0.00704. There are 1 homozygotes in GnomAd4. There are 77 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 77 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002547.3. 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
	OPHN1	NM_002547.3	MANE Select	c.2324+10G>T		intron	N/A	NP_002538.1	O60890-1
	OPHN1	NM_001437258.1		c.2000+10G>T		intron	N/A	NP_001424187.1	A0A7P0Z4E9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPHN1	ENST00000355520.6	TSL:1 MANE Select	c.2324+10G>T		intron	N/A	ENSP00000347710.5	O60890-1
	OPHN1	ENST00000905069.1		c.2324+10G>T		intron	N/A	ENSP00000575128.1
	OPHN1	ENST00000681408.1		c.2219+10G>T		intron	N/A	ENSP00000506619.1	A0A7P0TBH4

Frequencies

GnomAD3 genomes AF: 0.00238 AC: 266 AN: 111752 Hom.: 1 Cov.: 22

Gnomad AFR AF: 0.00784

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00143

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0168

Gnomad NFE AF: 0.0000564

Gnomad OTH AF: 0.00201

GnomAD2 exomes AF: 0.000731 AC: 132 AN: 180657 AF XY: 0.000566

Gnomad AFR exome AF: 0.00885

Gnomad AMR exome AF: 0.000293

Gnomad ASJ exome AF: 0.000135

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000621

Gnomad OTH exome AF: 0.000670

GnomAD4 exome AF: 0.000281 AC: 308 AN: 1096828 Hom.: 0 Cov.: 30 AF XY: 0.000226 AC XY: 82 AN XY: 362266

African (AFR) AF: 0.00875 AC: 231 AN: 26385

American (AMR) AF: 0.000455 AC: 16 AN: 35191

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19367

East Asian (EAS) AF: 0.00 AC: 0 AN: 30174

South Asian (SAS) AF: 0.00 AC: 0 AN: 53902

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40449

Middle Eastern (MID) AF: 0.000484 AC: 2 AN: 4134

European-Non Finnish (NFE) AF: 0.0000178 AC: 15 AN: 841175

Other (OTH) AF: 0.000955 AC: 44 AN: 46051

GnomAD4 genome AF: 0.00239 AC: 267 AN: 111804 Hom.: 1 Cov.: 22 AF XY: 0.00226 AC XY: 77 AN XY: 34004

African (AFR) AF: 0.00786 AC: 242 AN: 30803

American (AMR) AF: 0.00143 AC: 15 AN: 10524

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3523

South Asian (SAS) AF: 0.00 AC: 0 AN: 2644

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6101

Middle Eastern (MID) AF: 0.0184 AC: 4 AN: 217

European-Non Finnish (NFE) AF: 0.0000564 AC: 3 AN: 53146

Other (OTH) AF: 0.00199 AC: 3 AN: 1508

Alfa AF: 0.000879 Hom.: 8

Bravo AF: 0.00291

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	18
DANN	Benign	0.41
PhyloP100		-0.52
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.57		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.57		Position offset: 2

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

Other links and lift over

dbSNP: rs144475530; hg19: chrX-67273477;