rs121917880
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate
The NM_005413.4(SIX3):āc.749T>Cā(p.Val250Ala) variant causes a missense change involving the alteration of a conserved nucleotide. 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 (ā ).
Frequency
Genomes: not found (cov: 32)
Exomes š: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
SIX3
NM_005413.4 missense
NM_005413.4 missense
Scores
13
5
1
Clinical Significance
Conservation
PhyloP100: 7.75
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 10 ACMG points.
PM1
In a DNA_binding_region Homeobox (size 59) in uniprot entity SIX3_HUMAN there are 14 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, 0.994
PP5
Variant 2-44942853-T-C is Pathogenic according to our data. Variant chr2-44942853-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 6095.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SIX3 | NM_005413.4 | c.749T>C | p.Val250Ala | missense_variant | 1/2 | ENST00000260653.5 | NP_005404.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SIX3 | ENST00000260653.5 | c.749T>C | p.Val250Ala | missense_variant | 1/2 | 1 | NM_005413.4 | ENSP00000260653.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1446972Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 720224
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
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0
AN:
1446972
Hom.:
Cov.:
33
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AC XY:
0
AN XY:
720224
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Holoprosencephaly 2 Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2004 | - - |
Pathogenic, no assertion criteria provided | curation | GeneReviews | Aug 29, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | May 20, 2021 | The inherited missense heterozygous variant c.749T>C, p.Val250Ala, identified SIX1 has been reported with the variability of penetrance in multiple individuals and families with holoprosencephaly (PMID:10369266; PMID:15523651; PMID:19346217). This variant is not reported in the gnomAD v3.1 database, indicatinga rare allele, and in silico tools predict a deleterious effect. Functional studies demonstrated that this mutation resulted in the production of a highly unstable proteinin Neuro-2a cells (PMID:15523651). Based on the available evidence, the variant c.749T>C, p.Val250Ala in the SIX3 gene is classified as pathogenic. - |
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
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of disorder (P = 0.0152);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at