14-60648862-G-A

Variant names:

• chr14-60648862-G-A
• rs80356459
• NM_005982.4:c.328C>T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_005982.4(SIX1):​c.328C>T​(p.Arg110Trp) variant causes a missense change. 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R110Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SIX1 NM_005982.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 5.65
• Publications: 21 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 19 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, 7 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 chr14-60648861-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 420132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.989
• PP5: Variant 14-60648862-G-A is Pathogenic according to our data. Variant chr14-60648862-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 8309.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.328C>T	p.Arg110Trp	missense_variant	Exon 1 of 2	ENST00000645694.3	NP_005973.1
SIX1	NM_001425142.1	c.328C>T	p.Arg110Trp	missense_variant	Exon 1 of 2		NP_001412071.1
MIR9718	NR_162089.1	n.*151G>A		downstream_gene_variant
MIR9718	unassigned_transcript_2330	n.*162G>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIX1	ENST00000645694.3	c.328C>T	p.Arg110Trp	missense_variant	Exon 1 of 2		NM_005982.4	ENSP00000494686.1
SIX1	ENST00000554986.2	c.42-2285C>T		intron_variant	Intron 1 of 1	3		ENSP00000452700.2
SIX1	ENST00000553535.2	n.249-2285C>T		intron_variant	Intron 2 of 2	3
SIX1	ENST00000555955.3	n.1198-2285C>T		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Branchiootic syndrome 3 Pathogenic:1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

May 25, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 110 of the SIX1 protein (p.Arg110Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of SIX1-related conditions (PMID: 15141091, 24164807; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8309). 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, 31980437). This variant disrupts the p.Arg110 amino acid residue in SIX1. Other variant(s) that disrupt this residue have been determined to be pathogenic (internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Jun 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SIX1: PS1, PM2, PS3:Moderate, PP3, PS4:Supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	.;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H;H
PhyloP100		5.6
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-7.8	D;.
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;D
Vest4		0.91
MutPred		0.93		Loss of disorder (P = 0.0655);Loss of disorder (P = 0.0655);
MVP		0.98
MPC		2.5
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.97
gMVP		0.90
Mutation Taster		=7/93	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: rs80356459; hg19: chr14-61115580; COSMIC: COSV55960022; COSMIC: COSV55960022;