rs80356460

Variant summary

Our verdict is Pathogenic. Variant got 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

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 8.01
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1
In a DNA_binding_region Homeobox (size 59) in uniprot entity SIX1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) 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 [Likely_pathogenic]. Clinvar id is 8310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-60648790-TCTC-T is described in Lovd as [Likely_pathogenic]. Variant chr14-60648790-TCTC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SIX1NM_005982.4 linkc.397_399delGAG p.Glu133del conservative_inframe_deletion Exon 1 of 2 ENST00000645694.3 NP_005973.1 Q15475
SIX1NM_001425142.1 linkc.397_399delGAG p.Glu133del conservative_inframe_deletion Exon 1 of 2 NP_001412071.1
MIR9718NR_162089.1 linkn.*80_*82delCTC downstream_gene_variant
MIR9718unassigned_transcript_2330 n.*91_*93delCTC downstream_gene_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SIX1ENST00000645694.3 linkc.397_399delGAG p.Glu133del conservative_inframe_deletion Exon 1 of 2 NM_005982.4 ENSP00000494686.1 Q15475
SIX1ENST00000554986.2 linkc.42-2216_42-2214delGAG intron_variant Intron 1 of 1 3 ENSP00000452700.2 H0YK85
SIX1ENST00000553535.2 linkn.249-2216_249-2214delGAG intron_variant Intron 2 of 2 3
SIX1ENST00000555955.3 linkn.1198-2216_1198-2214delGAG intron_variant Intron 1 of 1 2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461870
Hom.:
0
AF XY:
0.00000138
AC XY:
1
AN XY:
727236
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Branchiootic syndrome 3 Pathogenic:4Other:1
-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Sep 01, 2022
3billion
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Inframe deletion located in a nonrepeat region is predicted to change the length of the protein and disrupt normal protein function. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 19497856). The variant has been reported to be associated with SIX1-related disorder (ClinVar ID: VCV000008310 / PMID: 15141091). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Feb 28, 2023
King Laboratory, University of Washington
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

This variant was found in heterozygosity in a patient and their mother, both with bilateral sensorineural hearing loss of onset <18 years, in a study of pediatric hearing loss conducted by the King Laboratory (Carlson RJ et al. JAMA-OtoHNS 2023). At the time of recruitment, both patients had preauricular ear pits, but had no other signs associated with branchio-oto-renal syndrome. This family has no other history of hearing loss outside of the proband and their mother. This variant is a three base pair deletion that results in the deletion of the glutamine residue at position 133 of the SIX1 protein. As of January 2023, this variant has been reported to ClinVar as pathogenic/likely pathogenic and is not found on gnomAD. Based on co-segregation with the phenotype in the family and goodness of fit of genotype to phenotype, we conclude that this variant is likely pathogenic. -

Aug 16, 2021
MGZ Medical Genetics Center
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 05, 2023
Laboratory of Otorhinolaryngology, Head and Neck Surgery, Seoul National University Hospital
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Branchiootic syndrome 3;C1854594:Autosomal dominant nonsyndromic hearing loss 23 Pathogenic:1
Aug 04, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant has been observed in individuals with branchiootorenal spectrum conditions and/or early onset deafness (PMID: 15141091, 36633841; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This variant, c.397_399del, results in the deletion of 1 amino acid(s) of the SIX1 protein (p.Glu133del), but otherwise preserves the integrity of the reading frame. This variant is also known as delE133. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this variant affects SIX1 function (PMID: 15141091, 19497856, 23435380). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 8310). -

not provided Pathogenic:1
Mar 21, 2023
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Functional studies demonstrate a damaging effect; variant results in diminished DNA binding and decreased lacZ activity (Ruf RG et al., 2004; Patrick AN et al., 2009); In-frame deletion of 1 amino acid in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15141091, 19497856, 33105617, 31595699) -

Autosomal dominant nonsyndromic hearing loss 23 Pathogenic:1
May 25, 2004
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs80356460; hg19: chr14-61115508; API