14-60648804-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_005982.4(SIX1):c.386A>G(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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y129S) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SIX1
NM_005982.4 missense

Scores

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]

SIX1 links:

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]

MIR9718 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_005982.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-60648805-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3382037.Status of the report is criteria_provided_single_submitter, 1 stars.

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 rank	MANE	Protein	UniProt
SIX1	NM_005982.4 link	c.386A>G	p.Tyr129Cys	missense_variant	Exon 1 of 2	ENST00000645694.3	NP_005973.1	Q15475
SIX1	NM_001425142.1 link	c.386A>G	p.Tyr129Cys	missense_variant	Exon 1 of 2		NP_001412071.1
MIR9718	NR_162089.1 link	n.*93T>C		downstream_gene_variant
MIR9718	unassigned_transcript_2330	n.*104T>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SIX1	ENST00000645694.3 link	c.386A>G	p.Tyr129Cys	missense_variant	Exon 1 of 2		NM_005982.4	ENSP00000494686.1	Q15475
SIX1	ENST00000554986.2 link	c.42-2227A>G		intron_variant	Intron 1 of 1	3		ENSP00000452700.2	H0YK85
SIX1	ENST00000553535.2 link	n.249-2227A>G		intron_variant	Intron 2 of 2	3
SIX1	ENST00000555955.3 link	n.1198-2227A>G		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251416

Hom.:

AF XY:

0.00

AC XY:

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:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00

AC XY:

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.:

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

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 29, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed 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) -

Branchiootic syndrome 3

Pathogenic:2Other:1

May 25, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 15, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant 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. -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Branchiootic syndrome 3;C1854594:Autosomal dominant nonsyndromic hearing loss 23;C4551702:Branchiootorenal syndrome 1

Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Branchiootic syndrome 3;C1854594:Autosomal dominant nonsyndromic hearing loss 23

Pathogenic:1

Aug 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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

Sep 01, 2017

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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

Nov 15, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The 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

May 01, 2024

Laboratory of Human Genetics, Universidade de São Paulo

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The 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

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

D;D

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

.;D

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.9

M;M

PrimateAI

Pathogenic

0.90

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over