chr2-44942123-CT-C
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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
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8
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1444074
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32
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4
AN XY:
718858
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 31
GnomAD4 genome
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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