14-60646494-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_005982.4(SIX1):c.644G>A(p.Ser215Asn) 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 benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S215I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: SIX1 NM_005982.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.57

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a chain Homeobox protein SIX1 (size 283) in uniprot entity SIX1_HUMAN there are 34 pathogenic changes around while only 10 benign (77%) in NM_005982.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40924078).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIX1	NM_005982.4	c.644G>A	p.Ser215Asn	missense_variant	2/2	ENST00000645694.3
SIX1	XM_017021602.3	c.*63G>A		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIX1	ENST00000645694.3	c.644G>A	p.Ser215Asn	missense_variant	2/2		NM_005982.4	P1
SIX1	ENST00000554986.2	c.125G>A	p.Ser42Asn	missense_variant	2/2	3
SIX1	ENST00000553535.2	n.332G>A		non_coding_transcript_exon_variant	3/3	3
SIX1	ENST00000555955.3	n.1281G>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249228 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 134894

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.41	T;T;T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	1.8	L;.;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.76	N;.;.
REVEL	Uncertain	0.35
Sift	Uncertain	0.011	D;.;.
Sift4G	Benign	0.083	T;D;.
Polyphen		0.70	P;.;P
Vest4		0.48
MutPred		0.17		Loss of phosphorylation at S215 (P = 0.0024);.;Loss of phosphorylation at S215 (P = 0.0024);
MVP		0.71
MPC		0.017
ClinPred		0.90	D
GERP RS		5.2
Varity_R		0.44
gMVP		0.59

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: rs540778343; hg19: chr14-61113212; COSMIC: COSV99903292; COSMIC: COSV99903292;