chr14-60648856-G-T

Position:

• chr14-60648856-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_005982.4(SIX1):​c.334C>A​(p.Arg112Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R112C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SIX1 NM_005982.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.01

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 8 ACMG points.

• PM1: In a helix (size 9) in uniprot entity SIX1_HUMAN there are 7 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 chr14-60648856-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.877

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIX1	NM_005982.4	c.334C>A	p.Arg112Ser	missense_variant	1/2	ENST00000645694.3	NP_005973.1
SIX1	XM_017021602.3	c.334C>A	p.Arg112Ser	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIX1	ENST00000645694.3	c.334C>A	p.Arg112Ser	missense_variant	1/2		NM_005982.4	ENSP00000494686.1
SIX1	ENST00000554986.2	c.42-2279C>A		intron_variant		3		ENSP00000452700.2
SIX1	ENST00000553535.2	n.249-2279C>A		intron_variant		3
SIX1	ENST00000555955.3	n.1198-2279C>A		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	1.0	.;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.7	H;H
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.8	D;.
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0010	D;.
Polyphen		1.0	D;D
Vest4		0.74
MutPred		0.61		Gain of phosphorylation at R112 (P = 0.0276);Gain of phosphorylation at R112 (P = 0.0276);
MVP		0.94
MPC		2.5
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.99
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-61115574;