X-68212079-C-T

Variant names:

• chrX-68212079-C-T
• rs3788859
• NM_002547.3:c.702+29G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002547.3(OPHN1):​c.702+29G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 1,035,682 control chromosomes in the GnomAD database, including 4,372 homozygotes. There are 32,959 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (617 hom., 3892 hem., cov: 23)
  • Exomes 𝑓: 0.10 (3755 hom. 29067 hem.)
• Consequence: OPHN1 NM_002547.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.847
• Publications: 4 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant X-68212079-C-T is Benign according to our data. Variant chrX-68212079-C-T is described in ClinVar as Benign. ClinVar VariationId is 159479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

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.702+29G>A		intron	N/A	NP_002538.1
	OPHN1	NM_001437258.1		c.702+29G>A		intron	N/A	NP_001424187.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPHN1	ENST00000355520.6	TSL:1 MANE Select	c.702+29G>A		intron	N/A	ENSP00000347710.5
	OPHN1	ENST00000905069.1		c.702+29G>A		intron	N/A	ENSP00000575128.1
	OPHN1	ENST00000681408.1		c.597+1783G>A		intron	N/A	ENSP00000506619.1

Frequencies

GnomAD3 genomes AF: 0.119 AC: 13253 AN: 111072 Hom.: 610 Cov.: 23

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.0830

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.128

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.0953

Gnomad MID AF: 0.131

Gnomad NFE AF: 0.0915

Gnomad OTH AF: 0.134

GnomAD2 exomes AF: 0.132 AC: 19548 AN: 148455 AF XY: 0.134

Gnomad AFR exome AF: 0.155

Gnomad AMR exome AF: 0.199

Gnomad ASJ exome AF: 0.145

Gnomad EAS exome AF: 0.132

Gnomad FIN exome AF: 0.0919

Gnomad NFE exome AF: 0.0921

Gnomad OTH exome AF: 0.133

GnomAD4 exome AF: 0.103 AC: 95461 AN: 924557 Hom.: 3755 Cov.: 15 AF XY: 0.112 AC XY: 29067 AN XY: 259273

African (AFR) AF: 0.152 AC: 3487 AN: 22900

American (AMR) AF: 0.195 AC: 6324 AN: 32393

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 2536 AN: 17917

East Asian (EAS) AF: 0.112 AC: 3220 AN: 28653

South Asian (SAS) AF: 0.195 AC: 9410 AN: 48294

European-Finnish (FIN) AF: 0.0905 AC: 3556 AN: 39305

Middle Eastern (MID) AF: 0.126 AC: 480 AN: 3812

European-Non Finnish (NFE) AF: 0.0892 AC: 61619 AN: 690874

Other (OTH) AF: 0.120 AC: 4829 AN: 40409

GnomAD4 genome AF: 0.119 AC: 13276 AN: 111125 Hom.: 617 Cov.: 23 AF XY: 0.117 AC XY: 3892 AN XY: 33393

African (AFR) AF: 0.152 AC: 4655 AN: 30584

American (AMR) AF: 0.150 AC: 1567 AN: 10481

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 358 AN: 2635

East Asian (EAS) AF: 0.128 AC: 446 AN: 3494

South Asian (SAS) AF: 0.204 AC: 538 AN: 2638

European-Finnish (FIN) AF: 0.0953 AC: 563 AN: 5910

Middle Eastern (MID) AF: 0.130 AC: 28 AN: 215

European-Non Finnish (NFE) AF: 0.0915 AC: 4847 AN: 52971

Other (OTH) AF: 0.143 AC: 218 AN: 1522

Alfa AF: 0.108 Hom.: 6933

Bravo AF: 0.128

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.86
DANN	Benign	0.68
PhyloP100		0.85
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3788859; hg19: chrX-67431921; COSMIC: COSV62781087; COSMIC: COSV62781087;