14-60648804-T-G

Variant names:

• chr14-60648804-T-G
• rs104894478
• NM_005982.4:c.386A>C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_005982.4(SIX1):​c.386A>C​(p.Tyr129Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y129C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SIX1 NM_005982.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 8.01

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 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 chr14-60648804-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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909
• PP5: Variant 14-60648804-T-G is Pathogenic according to our data. Variant chr14-60648804-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 666609.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIX1	NM_005982.4	c.386A>C	p.Tyr129Ser	missense_variant	Exon 1 of 2	ENST00000645694.3	NP_005973.1
SIX1	NM_001425142.1	c.386A>C	p.Tyr129Ser	missense_variant	Exon 1 of 2		NP_001412071.1
MIR9718	NR_162089.1	n.*93T>G		downstream_gene_variant
MIR9718	unassigned_transcript_2330	n.*104T>G		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIX1	ENST00000645694.3	c.386A>C	p.Tyr129Ser	missense_variant	Exon 1 of 2		NM_005982.4	ENSP00000494686.1
SIX1	ENST00000554986.2	c.42-2227A>C		intron_variant	Intron 1 of 1	3		ENSP00000452700.2
SIX1	ENST00000553535.2	n.249-2227A>C		intron_variant	Intron 2 of 2	3
SIX1	ENST00000555955.3	n.1198-2227A>C		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Branchiootic syndrome 3;C1854594:Autosomal dominant nonsyndromic hearing loss 23 Pathogenic:1 Uncertain:1

Jun 01, 2018

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 129 of the SIX1 protein (p.Tyr129Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with deafness (PMID: 34440452). ClinVar contains an entry for this variant (Variation ID: 666609). 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%. This variant disrupts the p.Tyr129 amino acid residue in SIX1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12843324, 15141091, 16652090, 21254961, 21280147). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Branchiootic syndrome 1 Pathogenic:1

Jun 01, 2018

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Feb 13, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Tyr129Ser variant in SIX1 has not been previously reported in individuals with hearing lo ss or branchio-oto-renal syndrome. However, a different pathogenic missense var iant at the same amino acid position (c.386A>G, p.Tyr129Cys) has been reported i n 3 probands with branchio-oto-renal syndrome, segregated in >10 affected indivi duals from one family, and in vitro functional evidence supported a deleterious effect of the variant (Ito 2006, Noguchi 2011, Patrick 2009, Ruf 2003, Ruf 2004) . The p.Tyr129Ser variant was absent from population databases. Computational prediction tools and conservation analyses suggest that the p.Tyr129Ser variant may impact the protein, though this information is not predictive enough to dete rmine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied: PM2; PM5; PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D;D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-8.3	D;.
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0020	D;.
Polyphen		1.0	D;D
Vest4		0.69
MutPred		0.53		Gain of disorder (P = 0.0079);Gain of disorder (P = 0.0079);
MVP		0.92
MPC		2.7
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.96
gMVP		0.88

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

Other links and lift over

dbSNP: rs104894478; hg19: chr14-61115522;