rs2148827

Variant names:

• chrX-68048534-C-A
• rs2148827
• NM_002547.3:c.2376-77G>T

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.2376-77G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 918,108 control chromosomes in the GnomAD database, including 5,113 homozygotes. There are 31,708 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1062 hom., 4526 hem., cov: 23)
  • Exomes 𝑓: 0.11 (4051 hom. 27182 hem.)
• Consequence: OPHN1 NM_002547.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0960
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant X-68048534-C-A is Benign according to our data. Variant chrX-68048534-C-A is described in ClinVar as Benign. ClinVar VariationId is 674158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.266 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.2376-77G>T		intron	N/A	NP_002538.1	O60890-1
	OPHN1	NM_001437258.1		c.2052-77G>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.2376-77G>T		intron	N/A	ENSP00000347710.5	O60890-1
	OPHN1	ENST00000905069.1		c.2376-77G>T		intron	N/A	ENSP00000575128.1
	OPHN1	ENST00000681408.1		c.2271-77G>T		intron	N/A	ENSP00000506619.1	A0A7P0TBH4

Frequencies

GnomAD3 genomes AF: 0.139 AC: 15469 AN: 111510 Hom.: 1054 Cov.: 23

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.0203

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.0753

Gnomad EAS AF: 0.281

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.0338

Gnomad MID AF: 0.113

Gnomad NFE AF: 0.0792

Gnomad OTH AF: 0.160

GnomAD4 exome AF: 0.108 AC: 87091 AN: 806544 Hom.: 4051 AF XY: 0.129 AC XY: 27182 AN XY: 210642

African (AFR) AF: 0.246 AC: 5091 AN: 20670

American (AMR) AF: 0.223 AC: 7494 AN: 33665

Ashkenazi Jewish (ASJ) AF: 0.0807 AC: 1409 AN: 17454

East Asian (EAS) AF: 0.234 AC: 6555 AN: 28046

South Asian (SAS) AF: 0.236 AC: 10964 AN: 46552

European-Finnish (FIN) AF: 0.0370 AC: 1462 AN: 39493

Middle Eastern (MID) AF: 0.110 AC: 392 AN: 3570

European-Non Finnish (NFE) AF: 0.0845 AC: 49084 AN: 580671

Other (OTH) AF: 0.127 AC: 4640 AN: 36423

GnomAD4 genome AF: 0.139 AC: 15495 AN: 111564 Hom.: 1062 Cov.: 23 AF XY: 0.134 AC XY: 4526 AN XY: 33776

African (AFR) AF: 0.230 AC: 7050 AN: 30596

American (AMR) AF: 0.185 AC: 1949 AN: 10554

Ashkenazi Jewish (ASJ) AF: 0.0753 AC: 199 AN: 2643

East Asian (EAS) AF: 0.281 AC: 975 AN: 3472

South Asian (SAS) AF: 0.232 AC: 609 AN: 2625

European-Finnish (FIN) AF: 0.0338 AC: 207 AN: 6124

Middle Eastern (MID) AF: 0.115 AC: 25 AN: 218

European-Non Finnish (NFE) AF: 0.0792 AC: 4205 AN: 53115

Other (OTH) AF: 0.171 AC: 262 AN: 1529

Alfa AF: 0.103 Hom.: 2358

Bravo AF: 0.160

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.2
DANN	Benign	0.45
PhyloP100		0.096
Mutation Taster		=100/0	polymorphism (auto)

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: rs2148827; hg19: chrX-67268376; COSMIC: COSV62781940;