14-60648862-G-A

Position:

• chr14-60648862-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 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. 12/21 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. R110G) 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a helix (size 9) in uniprot entity SIX1_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) 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 chr14-60648862-G-C is described in Lovd as [Pathogenic].
• 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. Variant chr14-60648862-G-A is described in Lovd as [Pathogenic]. Variant chr14-60648862-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIX1	NM_005982.4	c.328C>T	p.Arg110Trp	missense_variant	1/2	ENST00000645694.3	NP_005973.1
SIX1	XM_017021602.3	c.328C>T	p.Arg110Trp	missense_variant	1/2		XP_016877091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIX1	ENST00000645694.3	c.328C>T	p.Arg110Trp	missense_variant	1/2		NM_005982.4	ENSP00000494686	P1
SIX1	ENST00000554986.2	c.42-2285C>T		intron_variant		3		ENSP00000452700
SIX1	ENST00000553535.2	n.249-2285C>T		intron_variant, non_coding_transcript_variant		3
SIX1	ENST00000555955.3	n.1198-2285C>T		intron_variant, non_coding_transcript_variant		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

Pathogenic, no assertion criteria provided	literature only	OMIM	May 25, 2004	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 15, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg110 amino acid residue in SIX1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects SIX1 function (PMID: 15141091, 19497856, 31980437). 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. ClinVar contains an entry for this variant (Variation ID: 8309). This missense change has been observed in individuals with clinical features of SIX1-related conditions (PMID: 15141091, 24164807; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). 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). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2022

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
MutationTaster	Benign	1.0	A;A;A;A
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

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: rs80356459; hg19: chr14-61115580; COSMIC: COSV55960022; COSMIC: COSV55960022;