chr14-60648817-C-T

Variant names:

• chr14-60648817-C-T
• rs797044960
• NM_005982.4:c.373G>A

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_005982.4(SIX1):​c.373G>A​(p.Glu125Lys) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SIX1 NM_005982.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 7.90
• Publications: 6 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]

ACMG classification

Our verdict: Pathogenic. The variant received 15 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
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Trascript score misZ: 1.0225 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal dominant nonsyndromic hearing loss 23, branchiootic syndrome 3, branchio-oto-renal syndrome, autosomal dominant nonsyndromic hearing loss, branchiootic syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.88
• PP5: Variant 14-60648817-C-T is Pathogenic according to our data. Variant chr14-60648817-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 208361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIX1	NM_005982.4	c.373G>A	p.Glu125Lys	missense_variant	Exon 1 of 2	ENST00000645694.3	NP_005973.1
SIX1	NM_001425142.1	c.373G>A	p.Glu125Lys	missense_variant	Exon 1 of 2		NP_001412071.1
MIR9718	NR_162089.1	n.*106C>T		downstream_gene_variant
MIR9718	unassigned_transcript_2330	n.*117C>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIX1	ENST00000645694.3	c.373G>A	p.Glu125Lys	missense_variant	Exon 1 of 2		NM_005982.4	ENSP00000494686.1
SIX1	ENST00000554986.2	c.42-2240G>A		intron_variant	Intron 1 of 1	3		ENSP00000452700.2
SIX1	ENST00000553535.2	n.249-2240G>A		intron_variant	Intron 2 of 2	3
SIX1	ENST00000555955.3	n.1198-2240G>A		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 23 Pathogenic:2

May 22, 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. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.79; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with SIX1 related disorder (ClinVar ID: VCV000208361 / PMID: 21700001).The variant has been reported to co-segregate with the disease in at least 5 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 21700001). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Sep 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Branchiootic syndrome 3 Pathogenic:1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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

May 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 125 of the SIX1 protein (p.Glu125Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SIX1-related conditions (PMID: 21700001, 37479820). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 208361). 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: 37479820). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D;D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Pathogenic	3.3	M;M
PhyloP100		7.9
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.6	D;.
REVEL	Pathogenic	0.79
Sift	Uncertain	0.012	D;.
Sift4G	Uncertain	0.020	D;.
Polyphen		0.94	P;P
Vest4		0.91
MutPred		0.48		Gain of MoRF binding (P = 0.0019);Gain of MoRF binding (P = 0.0019);
MVP		0.98
MPC		2.3
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.70
gMVP		0.75
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs797044960; hg19: chr14-61115535;