chr7-101816094-G-A
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_ModeratePM2PP3_ModeratePP5
The NM_001913.5(CUX1):c.63+1G>A variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 29)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
CUX1
NM_001913.5 splice_donor
NM_001913.5 splice_donor
Scores
3
2
2
Splicing: ADA: 0.2711
2
Clinical Significance
Conservation
PhyloP100: 3.10
Genes affected
CUX1 (HGNC:2557): (cut like homeobox 1) The protein encoded by this gene is a member of the homeodomain family of DNA binding proteins. It may regulate gene expression, morphogenesis, and differentiation and it may also play a role in the cell cycle progession. Several alternatively spliced transcript variants encoding different isoforms have been identified.[provided by RefSeq, Feb 2011]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.04221895 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP3
BayesDel_addAF computational evidence supports a deleterious effect, 0.273
PP5
Variant 7-101816094-G-A is Pathogenic according to our data. Variant chr7-101816094-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 977603.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CUX1 | NM_001913.5 | c.63+1G>A | splice_donor_variant | ENST00000622516.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CUX1 | ENST00000622516.6 | c.63+1G>A | splice_donor_variant | 1 | NM_001913.5 |
Frequencies
GnomAD3 genomes Cov.: 29
GnomAD3 genomes
Cov.:
29
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1229628Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 612164
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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0
AN:
1229628
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30
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0
AN XY:
612164
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 29
GnomAD4 genome
Cov.:
29
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Intellectual disability Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Aug 03, 2020 | The variant c.63+1G>A, p.? was identified in an individual with neurodevelopmental disorder (NDD) and classified as Pathogenic according to ACMG guidelines. Inheritance for this variant was unknown.The variant likely explains the NDD in this individual. - |
Global developmental delay with or without impaired intellectual development Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
MutationTaster
Benign
D;D;D;D;D;D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
Find out detailed SpliceAI scores and Pangolin per-transcript scores at