rs104894478

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_005982.4(SIX1):ā€‹c.386A>Gā€‹(p.Tyr129Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,880 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 Pathogenic (ā˜…ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

SIX1
NM_005982.4 missense

Scores

14
4
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10O: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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 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;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.984
PP5
Variant 14-60648804-T-C is Pathogenic according to our data. Variant chr14-60648804-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 8308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-60648804-T-C is described in Lovd as [Pathogenic]. Variant chr14-60648804-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SIX1NM_005982.4 linkuse as main transcriptc.386A>G p.Tyr129Cys missense_variant 1/2 ENST00000645694.3 NP_005973.1
SIX1XM_017021602.3 linkuse as main transcriptc.386A>G p.Tyr129Cys missense_variant 1/2 XP_016877091.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SIX1ENST00000645694.3 linkuse as main transcriptc.386A>G p.Tyr129Cys missense_variant 1/2 NM_005982.4 ENSP00000494686 P1
SIX1ENST00000554986.2 linkuse as main transcriptc.42-2227A>G intron_variant 3 ENSP00000452700
SIX1ENST00000553535.2 linkuse as main transcriptn.249-2227A>G intron_variant, non_coding_transcript_variant 3
SIX1ENST00000555955.3 linkuse as main transcriptn.1198-2227A>G intron_variant, non_coding_transcript_variant 2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251416
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135904
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461880
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
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
Bravo
AF:
0.00000378

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:10Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingGeneDxJun 29, 2023Observed in multiple unrelated patients from different ethnic backgrounds with clinical features of branchiootorenal spectrum disorder (Ruf et al., 2004; Ito et al., 2006; Krug et al., 2011; Noguchi et al., 2011); Published functional studies demonstrate a damaging effect with deficient DNA binding (Ruf et al., 2004; Patrick et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15141091, 19497856, 34208995, 31980437, 31595699, 16652090, 21280147, 21254961, 25326635) -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Branchiootic syndrome 3 Pathogenic:2Other:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 25, 2004- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJul 15, 2022Variant summary: SIX1 c.386A>G (p.Tyr129Cys) results in a non-conservative amino acid change located in the Homeobox domain (IPR001356) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251416 control chromosomes (gnomAD). c.386A>G has been reported in the literature in multiple individuals affected with Branchiootic Syndrome 3 and fully co-segregated with disease in a large kindred (Ruf_2004, Ito_2006, Noguchi_2011, Nishio_2015). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant significantly reduced the binding activity of Six1 to DNA, and inhibited the ability of the SIX1-EYA complex to activate transcription (Ruf_2004, Patrick_2009). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided, no classification providedliterature onlyGeneReviews-- -
Branchiootic syndrome 3;C1854594:Autosomal dominant nonsyndromic hearing loss 23;C4551702:Branchiootorenal syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
Branchiootic syndrome 3;C1854594:Autosomal dominant nonsyndromic hearing loss 23 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 23, 2023This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 129 of the SIX1 protein (p.Tyr129Cys). This variant is present in population databases (rs104894478, gnomAD 0.007%). This missense change has been observed in individuals with branchiootorenal spectrum disorders (PMID: 12843324, 15141091, 16652090, 21254961, 21280147). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8308). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SIX1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SIX1 function (PMID: 15141091, 19497856). For these reasons, this variant has been classified as Pathogenic. -
Autosomal dominant nonsyndromic hearing loss 23 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsSep 01, 2017This variant has been previously reported as disease-causing and was found once in our laboratory de novo in a 5-year-old female with bilateral mild-to-moderate sensorineural hearing loss & preauricular pits; father & paternal grandfather had adult-onset conductive hearing loss; mother had preauricular pit -
SIX1-related disorder Pathogenic:1
Likely pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesNov 15, 2023The SIX1 c.386A>G variant is predicted to result in the amino acid substitution p.Tyr129Cys. This variant has been reported to segregate with branchiootic syndrome (BOS) in one large family with 18 affected individuals and was also found in two additional individuals with BOS from two unrelated families (Ruf et al. 2004. PubMed ID: 15141091; Ito et al. 2006. PubMed ID: 16652090; Noguchi et al. 2011. PubMed ID: 21254961). Functional experiments found this variant reduced DNA binding activity (Ruf et al. 2004. PubMed ID: 15141091; Patrick et al. 2009. PubMed ID: 19497856). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-61115522-T-C). This variant is interpreted as likely pathogenic. -
Branchiootic syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterresearchLaboratory of Human Genetics, Universidade de SĆ£o PauloMay 01, 2024The SIX1:c.386A>G: p.Tyr129Cys variant has well-established functional studies that show damaging effect on the gene or gene product (PS3), PS2, Non-truncating non-synonymous variant is located in a mutational hotspot and/or critical and well-established functional domain (PM1), Extremely low frequency in gnomAD population databases (PM2), Different amino acid change as a known pathogenic variant (PM5), Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1), computational prediction tools unanimously support a deleterious effect on the gene (PP3), Reported in ClinVar in affected cases (PP5). In our case it was found in one affected individual in heterozygosis, probably inherited from untested affected father. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.44
CADD
Pathogenic
34
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.91
D;D
Eigen
Pathogenic
0.94
Eigen_PC
Pathogenic
0.90
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
.;D
M_CAP
Pathogenic
0.45
D
MetaRNN
Pathogenic
0.98
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.9
M;M
MutationTaster
Benign
1.0
A;A;A;A
PrimateAI
Pathogenic
0.90
D
PROVEAN
Pathogenic
-8.3
D;.
REVEL
Pathogenic
0.95
Sift
Uncertain
0.0010
D;.
Sift4G
Uncertain
0.0030
D;.
Polyphen
1.0
D;D
Vest4
0.75
MutPred
0.88
Loss of phosphorylation at Y129 (P = 0.0483);Loss of phosphorylation at Y129 (P = 0.0483);
MVP
0.97
MPC
2.6
ClinPred
1.0
D
GERP RS
6.0
Varity_R
0.92
gMVP
0.85

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: rs104894478; hg19: chr14-61115522; API