rs397515376
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM4PP3PP5
The NM_000193.4(SHH):c.1132_1140del(p.Ala378_Phe380del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: not found (cov: 32)
Consequence
SHH
NM_000193.4 inframe_deletion
NM_000193.4 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.13
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 Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_000193.4.
PP3
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
PP5
Variant 7-155803148-GGAAGGGCGC-G is Pathogenic according to our data. Variant chr7-155803148-GGAAGGGCGC-G is described in ClinVar as [Pathogenic]. Clinvar id is 8889.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SHH | NM_000193.4 | c.1132_1140del | p.Ala378_Phe380del | inframe_deletion | 3/3 | ENST00000297261.7 | NP_000184.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SHH | ENST00000297261.7 | c.1132_1140del | p.Ala378_Phe380del | inframe_deletion | 3/3 | 1 | NM_000193.4 | ENSP00000297261 | P1 | |
SHH | ENST00000430104.5 | c.302-2912_302-2904del | intron_variant | 1 | ENSP00000396621 | |||||
SHH | ENST00000435425.1 | c.302-2560_302-2552del | intron_variant, NMD_transcript_variant | 1 | ENSP00000413871 | |||||
SHH | ENST00000441114.5 | c.302-2490_302-2482del | intron_variant, NMD_transcript_variant | 1 | ENSP00000410546 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Holoprosencephaly 3 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1999 | - - |
Pathogenic, no assertion criteria provided | curation | GeneReviews | Aug 29, 2013 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at