chr7-101816094-G-A

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

Scores

3
2
2
Splicing: ADA: 0.2711
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 3.10
Variant links:
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
CUX1NM_001913.5 linkuse as main transcriptc.63+1G>A splice_donor_variant ENST00000622516.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CUX1ENST00000622516.6 linkuse as main transcriptc.63+1G>A splice_donor_variant 1 NM_001913.5 Q13948-1

Frequencies

GnomAD3 genomes
Cov.:
29
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1229628
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
612164
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
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 submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterAug 03, 2020The 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 submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterJan 01, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.15
CADD
Benign
22
DANN
Uncertain
0.98
Eigen
Pathogenic
0.83
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Benign
0.54
D
MutationTaster
Benign
1.0
D;D;D;D;D;D
GERP RS
1.4
RBP_binding_hub_radar
0.67
RBP_regulation_power_radar
1.9

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.27
dbscSNV1_RF
Benign
0.44

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1791729069; hg19: chr7-101459374; API