Genetic Variant NM_002547.3:c.2401G>T (chrX-68048432-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The NM_002547.3(OPHN1):c.2401G>T(p.Glu801*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000274 in 1,096,755 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000027 ( 0 hom. 1 hem. )

Consequence

OPHN1
NM_002547.3 stop_gained

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.17

Publications

0 publications found

Variant links:

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)

OPHN1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00332 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

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.2401G>T	p.Glu801*	stop_gained	Exon 24 of 25	NP_002538.1	O60890-1
	OPHN1	NM_001437258.1		c.2077G>T	p.Glu693*	stop_gained	Exon 23 of 24	NP_001424187.1	A0A7P0Z4E9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OPHN1	ENST00000355520.6	TSL:1 MANE Select	c.2401G>T	p.Glu801*	stop_gained	Exon 24 of 25	ENSP00000347710.5	O60890-1
OPHN1	ENST00000905069.1		c.2401G>T	p.Glu801*	stop_gained	Exon 24 of 25	ENSP00000575128.1
OPHN1	ENST00000681408.1		c.2296G>T	p.Glu766*	stop_gained	Exon 23 of 24	ENSP00000506619.1	A0A7P0TBH4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000548

AC:

AN:

182546

AF XY:

0.0000149

show subpopulations

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:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1096755

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

362195

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26373

American (AMR)

AF:

0.00

AC:

AN:

35186

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19375

East Asian (EAS)

AF:

0.00

AC:

AN:

30174

South Asian (SAS)

AF:

0.00

AC:

AN:

54058

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40498

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4133

European-Non Finnish (NFE)

AF:

0.00000357

AC:

AN:

840911

Other (OTH)

AF:

0.00

AC:

AN:

46047

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

FATHMM_MKL

Uncertain

0.91

PhyloP100

4.2

Vest4

0.61

GERP RS

4.7

Mutation Taster

=86/114

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over