dbSNP rs540778343: SIX1:p.Ser215Ile (chr14-60646494-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_005982.4(SIX1):c.644G>T(p.Ser215Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SIX1
NM_005982.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.57

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a chain Homeobox protein SIX1 (size 283) in uniprot entity SIX1_HUMAN there are 18 pathogenic changes around while only 5 benign (78%) in NM_005982.4

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIX1	NM_005982.4 link	c.644G>T	p.Ser215Ile	missense_variant	Exon 2 of 2	ENST00000645694.3	NP_005973.1	Q15475
SIX1	NM_001425142.1 link	c.*63G>T		3_prime_UTR_variant	Exon 2 of 2		NP_001412071.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SIX1	ENST00000645694.3 link	c.644G>T	p.Ser215Ile	missense_variant	Exon 2 of 2		NM_005982.4	ENSP00000494686.1	Q15475
SIX1	ENST00000554986.2 link	c.125G>T	p.Ser42Ile	missense_variant	Exon 2 of 2	3		ENSP00000452700.2	H0YK85
SIX1	ENST00000553535.2 link	n.332G>T		non_coding_transcript_exon_variant	Exon 3 of 3	3
SIX1	ENST00000555955.3 link	n.1281G>T		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Uncertain:1

Apr 25, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). This sequence change replaces serine with isoleucine at codon 215 of the SIX1 protein (p.Ser215Ile). The serine residue is highly conserved and there is a large physicochemical difference between serine and isoleucine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SIX1-related disease. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

T;T;T

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.88

.;D;D

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.57

D;D;D

MetaSVM

Uncertain

0.47

MutationAssessor

Benign

1.8

L;.;L

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.4

N;.;.

REVEL

Uncertain

0.60

Sift

Uncertain

0.0040

D;.;.

Sift4G

Uncertain

0.024

D;D;.

Polyphen

0.94

P;.;P

Vest4

0.71

MutPred

0.18

Loss of phosphorylation at S215 (P = 0.0024);.;Loss of phosphorylation at S215 (P = 0.0024);

MVP

0.82

MPC

0.096

ClinPred

0.96

GERP RS

5.2

Varity_R

0.52

gMVP

0.71

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over