chr14-60649140-A-T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PP2PP3_Strong

The NM_005982.4(SIX1):​c.50T>A​(p.Val17Glu) 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 not provided (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

SIX1
NM_005982.4 missense

Scores

17
1
1

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 9.29

Publications

16 publications found
Variant links:
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 Gene-Disease associations (from GenCC):
  • autosomal dominant nonsyndromic hearing loss 23
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P
  • branchio-oto-renal syndrome
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Orphanet
  • branchiootic syndrome 3
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
  • autosomal dominant nonsyndromic hearing loss
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • branchiootic syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM1
In a chain Homeobox protein SIX1 (size 283) in uniprot entity SIX1_HUMAN there are 20 pathogenic changes around while only 5 benign (80%) 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, 0.985

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SIX1NM_005982.4 linkc.50T>A p.Val17Glu missense_variant Exon 1 of 2 ENST00000645694.3 NP_005973.1 Q15475
SIX1NM_001425142.1 linkc.50T>A p.Val17Glu missense_variant Exon 1 of 2 NP_001412071.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SIX1ENST00000645694.3 linkc.50T>A p.Val17Glu missense_variant Exon 1 of 2 NM_005982.4 ENSP00000494686.1 Q15475
SIX1ENST00000554986.2 linkc.42-2563T>A intron_variant Intron 1 of 1 3 ENSP00000452700.2 H0YK85
SIX1ENST00000553535.2 linkn.249-2563T>A intron_variant Intron 2 of 2 3
SIX1ENST00000555955.3 linkn.1198-2563T>A intron_variant Intron 1 of 1 2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: not provided
Submissions summary: Other:1
Revision: no classification provided
LINK: link

Submissions by phenotype

Branchiootic syndrome 3 Other:1
-
GeneReviews
Significance:not provided
Review Status:no classification provided
Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.51
D
BayesDel_noAF
Pathogenic
0.50
CADD
Pathogenic
33
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.98
D;D
Eigen
Pathogenic
0.90
Eigen_PC
Pathogenic
0.82
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
.;D
M_CAP
Pathogenic
0.58
D
MetaRNN
Pathogenic
0.98
D;D
MetaSVM
Pathogenic
0.97
D
MutationAssessor
Pathogenic
3.5
M;M
PhyloP100
9.3
PrimateAI
Pathogenic
0.91
D
PROVEAN
Pathogenic
-5.3
D;.
REVEL
Pathogenic
0.93
Sift
Pathogenic
0.0
D;.
Sift4G
Pathogenic
0.0
D;.
Polyphen
1.0
D;D
Vest4
0.97
MutPred
0.88
Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);
MVP
0.99
MPC
3.0
ClinPred
1.0
D
GERP RS
4.6
PromoterAI
-0.0083
Neutral
Varity_R
0.98
gMVP
0.91
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

Publications

Other links and lift over

dbSNP: rs397515562; hg19: chr14-61115858; API