rs121917878
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_005413.4(SIX3):c.676C>G(p.Leu226Val) variant causes a missense change. 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 (no stars). Synonymous variant affecting the same amino acid position (i.e. L226L) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
SIX3
NM_005413.4 missense
NM_005413.4 missense
Scores
6
7
6
Clinical Significance
Conservation
PhyloP100: 4.77
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 Likely_pathogenic. Variant got 7 ACMG points.
PM1
?
In a DNA_binding_region Homeobox (size 59) in uniprot entity SIX3_HUMAN there are 19 pathogenic changes around while only 0 benign (100%) in NM_005413.4
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.879
PP5
?
Variant 2-44942780-C-G is Pathogenic according to our data. Variant chr2-44942780-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 6093.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SIX3 | NM_005413.4 | c.676C>G | p.Leu226Val | missense_variant | 1/2 | ENST00000260653.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SIX3 | ENST00000260653.5 | c.676C>G | p.Leu226Val | missense_variant | 1/2 | 1 | NM_005413.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
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 2 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2004 | - - |
Pathogenic, no assertion criteria provided | curation | GeneReviews | Aug 29, 2013 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Benign
N
MutationTaster
Benign
A
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Benign
D
Sift4G
Benign
T
Polyphen
B
Vest4
MutPred
Gain of MoRF binding (P = 0.0911);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -5
Find out detailed SpliceAI scores and Pangolin per-transcript scores at