rs121909770

chr14-60648826-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_005982.4(SIX1):c.364T>A(p.Trp122Arg) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SIX1 NM_005982.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.32

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_005982.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 14-60648826-A-T is Pathogenic according to our data. Variant chr14-60648826-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 8311.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr14-60648826-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIX1	NM_005982.4	c.364T>A	p.Trp122Arg	missense_variant	1/2	ENST00000645694.3
SIX1	XM_017021602.3	c.364T>A	p.Trp122Arg	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIX1	ENST00000645694.3	c.364T>A	p.Trp122Arg	missense_variant	1/2		NM_005982.4	P1
SIX1	ENST00000554986.2	c.42-2249T>A		intron_variant		3
SIX1	ENST00000553535.2	n.249-2249T>A		intron_variant, non_coding_transcript_variant		3
SIX1	ENST00000555955.3	n.1198-2249T>A		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:1

Revision: no assertion criteria provided

Submissions by phenotype

Branchiootic syndrome 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
Cadd	Pathogenic	34
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D;D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H;H
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-13	D;.
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		0.97	D;D
Vest4		0.90
MutPred		0.85		Gain of disorder (P = 0.0011);Gain of disorder (P = 0.0011);
MVP		0.97
MPC		3.1
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.93
gMVP		0.84

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: rs121909770; hg19: chr14-61115544;