rs765654561

Variant names:

• chrX-68274789-C-T
• rs765654561
• NM_002547.3:c.333G>A
• OPHN1 p.Leu111Leu

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_002547.3(OPHN1):​c.333G>A​(p.Leu111Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.00003 in 1,201,685 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000054 (0 hom., 3 hem., cov: 23)
  • Exomes 𝑓: 0.000028 (0 hom. 12 hem.)
• Consequence: OPHN1 NM_002547.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.71
• 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, G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant X-68274789-C-T is Benign according to our data. Variant chrX-68274789-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 211794.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000535 (6/112112) while in subpopulation SAS AF = 0.00188 (5/2661). AF 95% confidence interval is 0.00074. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 3 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.333G>A	p.Leu111Leu	synonymous	Exon 5 of 25	NP_002538.1	O60890-1
	OPHN1	NM_001437258.1		c.333G>A	p.Leu111Leu	synonymous	Exon 5 of 24	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.333G>A	p.Leu111Leu	synonymous	Exon 5 of 25	ENSP00000347710.5	O60890-1
	OPHN1	ENST00000905069.1		c.333G>A	p.Leu111Leu	synonymous	Exon 5 of 25	ENSP00000575128.1
	OPHN1	ENST00000681408.1		c.333G>A	p.Leu111Leu	synonymous	Exon 5 of 24	ENSP00000506619.1	A0A7P0TBH4

Frequencies

GnomAD3 genomes AF: 0.0000535 AC: 6 AN: 112058 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000662

GnomAD2 exomes AF: 0.0000985 AC: 18 AN: 182665 AF XY: 0.0000743

Gnomad AFR exome AF: 0.00

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: 0.00

Gnomad OTH exome AF: 0.000223

GnomAD4 exome AF: 0.0000275 AC: 30 AN: 1089573 Hom.: 0 Cov.: 26 AF XY: 0.0000337 AC XY: 12 AN XY: 355557

African (AFR) AF: 0.00 AC: 0 AN: 26234

American (AMR) AF: 0.00 AC: 0 AN: 35132

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19270

East Asian (EAS) AF: 0.00 AC: 0 AN: 30055

South Asian (SAS) AF: 0.000390 AC: 21 AN: 53853

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3931

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 835157

Other (OTH) AF: 0.000175 AC: 8 AN: 45753

GnomAD4 genome AF: 0.0000535 AC: 6 AN: 112112 Hom.: 0 Cov.: 23 AF XY: 0.0000874 AC XY: 3 AN XY: 34316

African (AFR) AF: 0.00 AC: 0 AN: 30890

American (AMR) AF: 0.00 AC: 0 AN: 10549

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2657

East Asian (EAS) AF: 0.00 AC: 0 AN: 3577

South Asian (SAS) AF: 0.00188 AC: 5 AN: 2661

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53241

Other (OTH) AF: 0.000654 AC: 1 AN: 1530

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	11
DANN	Benign	0.80
PhyloP100		4.7
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs765654561;

hg19: chrX-67494631;