rs1553878162
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_002448.3(MSX1):c.661C>T(p.Gln221Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 33)
Consequence
MSX1
NM_002448.3 stop_gained
NM_002448.3 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 7.77
Genes affected
MSX1 (HGNC:7391): (msh homeobox 1) This gene encodes a member of the muscle segment homeobox gene family. The encoded protein functions as a transcriptional repressor during embryogenesis through interactions with components of the core transcription complex and other homeoproteins. It may also have roles in limb-pattern formation, craniofacial development, particularly odontogenesis, and tumor growth inhibition. Mutations in this gene, which was once known as homeobox 7, have been associated with nonsyndromic cleft lip with or without cleft palate 5, Witkop syndrome, Wolf-Hirschom syndrome, and autosomoal dominant hypodontia. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 11 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 4-4862892-C-T is Pathogenic according to our data. Variant chr4-4862892-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 461602.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSX1 | NM_002448.3 | c.661C>T | p.Gln221Ter | stop_gained | 2/2 | ENST00000382723.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSX1 | ENST00000382723.5 | c.661C>T | p.Gln221Ter | stop_gained | 2/2 | 1 | NM_002448.3 | P1 | |
MSX1 | ENST00000468421.1 | n.373C>T | non_coding_transcript_exon_variant | 2/2 | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 34
GnomAD4 exome
Cov.:
34
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hypoplastic enamel-onycholysis-hypohidrosis syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 29, 2016 | In summary, this variant is a novel truncating variant that is expected to disrupt an essential region of the MSX1 protein. Therefore, it has been classified as Pathogenic. This variant has not been reported in the literature in individuals with a MSX1-related disease. However, a different truncation downstream of this variant (p.Asn222Lysfs*118) has been determined to be pathogenic (PMID: 23991204). This suggests that deletion of this region of the MSX1 protein is causative of disease. This sequence change results in a premature translational stop signal in the last exon of the MSX1 mRNA at codon 221 (p.Gln221*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 83 amino acids of the MSX1 protein. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at