rs771217604

Variant names:

• chrX-68053625-T-G
• rs771217604
• NM_002547.3:c.2324+20A>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_002547.3(OPHN1):​c.2324+20A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000663 in 1,206,798 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 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 0.0000089 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.0000064 (0 hom. 3 hem.)
• Consequence: OPHN1 NM_002547.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.965
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, ClinGen, G2P

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant X-68053625-T-G is Benign according to our data. Variant chrX-68053625-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2169148.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome4 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.2324+20A>C		intron	N/A	NP_002538.1	O60890-1
	OPHN1	NM_001437258.1		c.2000+20A>C		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+20A>C		intron	N/A	ENSP00000347710.5	O60890-1
	OPHN1	ENST00000905069.1		c.2324+20A>C		intron	N/A	ENSP00000575128.1
	OPHN1	ENST00000681408.1		c.2219+20A>C		intron	N/A	ENSP00000506619.1	A0A7P0TBH4

Frequencies

GnomAD3 genomes AF: 0.00000894 AC: 1 AN: 111826 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000325

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

GnomAD2 exomes AF: 0.00 AC: 0 AN: 179512 AF XY: 0.00

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: 0.00

GnomAD4 exome AF: 0.00000639 AC: 7 AN: 1094972 Hom.: 0 Cov.: 30 AF XY: 0.00000832 AC XY: 3 AN XY: 360486

African (AFR) AF: 0.00 AC: 0 AN: 26355

American (AMR) AF: 0.00 AC: 0 AN: 35177

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19355

East Asian (EAS) AF: 0.00 AC: 0 AN: 30166

South Asian (SAS) AF: 0.00 AC: 0 AN: 53756

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4130

European-Non Finnish (NFE) AF: 0.00000834 AC: 7 AN: 839635

Other (OTH) AF: 0.00 AC: 0 AN: 45978

GnomAD4 genome AF: 0.00000894 AC: 1 AN: 111826 Hom.: 0 Cov.: 23 AF XY: 0.0000294 AC XY: 1 AN XY: 33990

African (AFR) AF: 0.0000325 AC: 1 AN: 30779

American (AMR) AF: 0.00 AC: 0 AN: 10531

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2655

East Asian (EAS) AF: 0.00 AC: 0 AN: 3540

South Asian (SAS) AF: 0.00 AC: 0 AN: 2650

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6103

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53149

Other (OTH) AF: 0.00 AC: 0 AN: 1495

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.3
DANN	Benign	0.53
PhyloP100		0.96

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: rs771217604; hg19: chrX-67273467;