2-44942123-CT-C
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_005413.4(SIX3):c.20del(p.Leu7GlnfsTer244) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000055 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
SIX3
NM_005413.4 frameshift
NM_005413.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.70
Genes affected
SIX3 (HGNC:10889): (SIX homeobox 3) This gene encodes a member of the sine oculis homeobox transcription factor family. The encoded protein plays a role in eye development. Mutations in this gene have been associated with holoprosencephaly type 2. [provided by RefSeq, Oct 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 51 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 2-44942123-CT-C is Pathogenic according to our data. Variant chr2-44942123-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 2729808.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SIX3 | NM_005413.4 | c.20del | p.Leu7GlnfsTer244 | frameshift_variant | 1/2 | ENST00000260653.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SIX3 | ENST00000260653.5 | c.20del | p.Leu7GlnfsTer244 | frameshift_variant | 1/2 | 1 | NM_005413.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000554 AC: 8AN: 1444074Hom.: 0 Cov.: 32 AF XY: 0.00000556 AC XY: 4AN XY: 718858
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
8
AN:
1444074
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Cov.:
32
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AC XY:
4
AN XY:
718858
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GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
Bravo
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Holoprosencephaly 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 17, 2023 | This sequence change creates a premature translational stop signal (p.Leu7Glnfs*244) in the SIX3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SIX3 are known to be pathogenic (PMID: 18791198). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SIX3-related conditions. For these reasons, this variant has been classified as Pathogenic. - |
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