NM_005982.4:c.397_399delGAG
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong
The NM_005982.4(SIX1):c.397_399delGAG(p.Glu133del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
SIX1
NM_005982.4 conservative_inframe_deletion
NM_005982.4 conservative_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.01
Publications
8 publications found
Genes affected
SIX1 (HGNC:10887): (SIX homeobox 1) The protein encoded by this gene is a homeobox protein that is similar to the Drosophila 'sine oculis' gene product. This gene is found in a cluster of related genes on chromosome 14 and is thought to be involved in limb development. Defects in this gene are a cause of autosomal dominant deafness type 23 (DFNA23) and branchiootic syndrome type 3 (BOS3). [provided by RefSeq, Jul 2008]
MIR9718 (HGNC:53988): (microRNA 9718) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 13 ACMG points.
PM1
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_005982.4
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_005982.4. Strenght limited to Supporting due to length of the change: 1aa.
PP5
Variant 14-60648790-TCTC-T is Pathogenic according to our data. Variant chr14-60648790-TCTC-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 8310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_005982.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| SIX1 | MANE Select | c.397_399delGAG | p.Glu133del | conservative_inframe_deletion | Exon 1 of 2 | NP_005973.1 | Q15475 | ||
| SIX1 | c.397_399delGAG | p.Glu133del | conservative_inframe_deletion | Exon 1 of 2 | NP_001412071.1 | ||||
| MIR9718 | n.*80_*82delCTC | downstream_gene | N/A |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| SIX1 | MANE Select | c.397_399delGAG | p.Glu133del | conservative_inframe_deletion | Exon 1 of 2 | ENSP00000494686.1 | Q15475 | ||
| SIX1 | c.397_399delGAG | p.Glu133del | conservative_inframe_deletion | Exon 1 of 2 | ENSP00000619574.1 | ||||
| SIX1 | TSL:3 | c.42-2216_42-2214delGAG | intron | N/A | ENSP00000452700.2 | H0YK85 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461870Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727236 show subpopulations
GnomAD4 exome
AF:
AC:
2
AN:
1461870
Hom.:
AF XY:
AC XY:
1
AN XY:
727236
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33480
American (AMR)
AF:
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26136
East Asian (EAS)
AF:
AC:
1
AN:
39700
South Asian (SAS)
AF:
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
AC:
0
AN:
53406
Middle Eastern (MID)
AF:
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1112002
Other (OTH)
AF:
AC:
0
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic/Likely pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
4
-
-
Branchiootic syndrome 3 (5)
1
-
-
Autosomal dominant nonsyndromic hearing loss 23 (1)
1
-
-
Branchiootic syndrome 3;C1854594:Autosomal dominant nonsyndromic hearing loss 23 (1)
1
-
-
not provided (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
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
Publications
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