rs1554493617
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Strong
The NM_000193.4(SHH):c.1282del(p.Ala428ProfsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000029 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
SHH
NM_000193.4 frameshift
NM_000193.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.698
Genes affected
SHH (HGNC:10848): (sonic hedgehog signaling molecule) This gene encodes a protein that is instrumental in patterning the early embryo. It has been implicated as the key inductive signal in patterning of the ventral neural tube, the anterior-posterior limb axis, and the ventral somites. Of three human proteins showing sequence and functional similarity to the sonic hedgehog protein of Drosophila, this protein is the most similar. The protein is made as a precursor that is autocatalytically cleaved; the N-terminal portion is soluble and contains the signalling activity while the C-terminal portion is involved in precursor processing. More importantly, the C-terminal product covalently attaches a cholesterol moiety to the N-terminal product, restricting the N-terminal product to the cell surface and preventing it from freely diffusing throughout the developing embryo. Defects in this protein or in its signalling pathway are a cause of holoprosencephaly (HPE), a disorder in which the developing forebrain fails to correctly separate into right and left hemispheres. HPE is manifested by facial deformities. It is also thought that mutations in this gene or in its signalling pathway may be responsible for VACTERL syndrome, which is characterized by vertebral defects, anal atresia, tracheoesophageal fistula with esophageal atresia, radial and renal dysplasia, cardiac anomalies, and limb abnormalities. Additionally, mutations in a long range enhancer located approximately 1 megabase upstream of this gene disrupt limb patterning and can result in preaxial polydactyly. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 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 6 pathogenic variants in the truncated region.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SHH | NM_000193.4 | c.1282del | p.Ala428ProfsTer15 | frameshift_variant | 3/3 | ENST00000297261.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SHH | ENST00000297261.7 | c.1282del | p.Ala428ProfsTer15 | frameshift_variant | 3/3 | 1 | NM_000193.4 | P1 | |
SHH | ENST00000430104.5 | c.302-2762del | intron_variant | 1 | |||||
SHH | ENST00000435425.1 | c.302-2410del | intron_variant, NMD_transcript_variant | 1 | |||||
SHH | ENST00000441114.5 | c.302-2340del | intron_variant, NMD_transcript_variant | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000287 AC: 4AN: 1395094Hom.: 0 Cov.: 35 AF XY: 0.00000577 AC XY: 4AN XY: 693274
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
4
AN:
1395094
Hom.:
Cov.:
35
AF XY:
AC XY:
4
AN XY:
693274
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Acrocallosal syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Medical Genetics, University of Zurich | May 18, 2017 | - - |
Computational scores
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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