rs141368794
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2
The NM_002547.3(OPHN1):c.1613A>G(p.Asp538Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000331 in 1,208,260 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000054 ( 0 hom., 2 hem., cov: 22)
Exomes 𝑓: 0.000031 ( 0 hom. 10 hem. )
Consequence
OPHN1
NM_002547.3 missense
NM_002547.3 missense
Scores
3
5
9
Clinical Significance
Conservation
PhyloP100: 7.49
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.38885957).
BS2
?
High Hemizygotes in GnomAd at 2 XL gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OPHN1 | NM_002547.3 | c.1613A>G | p.Asp538Gly | missense_variant | 19/25 | ENST00000355520.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OPHN1 | ENST00000355520.6 | c.1613A>G | p.Asp538Gly | missense_variant | 19/25 | 1 | NM_002547.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000538 AC: 6AN: 111513Hom.: 0 Cov.: 22 AF XY: 0.0000593 AC XY: 2AN XY: 33719
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0000328 AC: 6AN: 183187Hom.: 0 AF XY: 0.0000148 AC XY: 1AN XY: 67687
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GnomAD4 exome AF: 0.0000310 AC: 34AN: 1096747Hom.: 0 Cov.: 30 AF XY: 0.0000276 AC XY: 10AN XY: 362229
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GnomAD4 genome ? AF: 0.0000538 AC: 6AN: 111513Hom.: 0 Cov.: 22 AF XY: 0.0000593 AC XY: 2AN XY: 33719
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 03, 2015 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 08, 2022 | The c.1613A>G (p.D538G) alteration is located in exon 19 (coding exon 18) of the OPHN1 gene. This alteration results from a A to G substitution at nucleotide position 1613, causing the aspartic acid (D) at amino acid position 538 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
X-linked intellectual disability-cerebellar hypoplasia syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 18, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Benign
Sift
Uncertain
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at