chr14-60648804-T-G

Position:

• chr14-60648804-T-G

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:1
• 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]

SIX1 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a DNA_binding_region Homeobox (size 59) in uniprot entity SIX1_HUMAN there are 5 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 chr14-60648804-T-C is described in Lovd as [Pathogenic].
• 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: {Uncertain_significance=1, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIX1	NM_005982.4	c.386A>C	p.Tyr129Ser	missense_variant	1/2	ENST00000645694.3	NP_005973.1
SIX1	XM_017021602.3	c.386A>C	p.Tyr129Ser	missense_variant	1/2

Ensembl

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Branchiootic syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center of Genomic medicine, Geneva, University Hospital of Geneva

Jun 01, 2018

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Center of Genomic medicine, Geneva, University Hospital of Geneva

Jun 01, 2018

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 13, 2018

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;