chr2-44942105-A-G
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_005413.4(SIX3):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000698 in 1,433,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 7.0e-7 ( 0 hom. )
Consequence
SIX3
NM_005413.4 start_lost
NM_005413.4 start_lost
Scores
7
4
5
Clinical Significance
Conservation
PhyloP100: 7.95
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
?
Start lost variant, no new inframe start found.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 2-44942105-A-G is Pathogenic according to our data. Variant chr2-44942105-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 504413.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.1A>G | p.Met1? | start_lost | 1/2 | ENST00000260653.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SIX3 | ENST00000260653.5 | c.1A>G | p.Met1? | start_lost | 1/2 | 1 | NM_005413.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome AF: 6.98e-7 AC: 1AN: 1433228Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1AN XY: 713614
GnomAD4 exome
AF:
AC:
1
AN:
1433228
Hom.:
Cov.:
31
AF XY:
AC XY:
1
AN XY:
713614
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 06, 2018 | The c.1 A>G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.1 A>G variant is not observed in large population cohorts (Lek et al., 2016). The c.1 A>G variant alters the initiator Methionine codon, and the resultant protein would be described as p.Met1?, using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Methionine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationTaster
Benign
D
PROVEAN
Benign
N
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Uncertain
D
Polyphen
P
Vest4
MutPred
Gain of sheet (P = 0.039);
MVP
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
Find out detailed SpliceAI scores and Pangolin per-transcript scores at