NM_005413.4:c.339G>T

Variant names:

• chr2-44942443-G-T
• rs137853021
• NM_005413.4:c.339G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_005413.4(SIX3):​c.339G>T​(p.Trp113Cys) 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. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W113S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SIX3 NM_005413.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.52
• Publications: 3 publications found

Genes affected

SIX3 (HGNC:10889): (SIX homeobox 3) This gene encodes a member of the sine oculis homeobox transcription factor family. The encoded protein plays a role in eye development. Mutations in this gene have been associated with holoprosencephaly type 2. [provided by RefSeq, Oct 2009]

ENSG00000225156 (HGNC:):

SIX3-AS1 (HGNC:40532): (SIX3 antisense RNA 1)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 2-44942443-G-T is Pathogenic according to our data. Variant chr2-44942443-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 6099.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005413.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIX3	NM_005413.4	MANE Select	c.339G>T	p.Trp113Cys	missense	Exon 1 of 2	NP_005404.1	O95343

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIX3	ENST00000260653.5	TSL:1 MANE Select	c.339G>T	p.Trp113Cys	missense	Exon 1 of 2	ENSP00000260653.3	O95343
	ENSG00000225156	ENST00000760330.1		n.135+8067G>T		intron	N/A
	SIX3-AS1	ENST00000760560.1		n.389-1610C>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Holoprosencephaly 2 (1)
1	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	34
DANN	Uncertain	0.97
DEOGEN2	Pathogenic	0.95	D
Eigen	Benign	0.14
Eigen_PC	Benign	0.10
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.3	L
PhyloP100		9.5
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-12	D
REVEL	Pathogenic	0.79
Sift	Benign	0.090	T
Sift4G	Uncertain	0.047	D
Polyphen		0.55	P
Vest4		0.94
MutPred		0.89		Gain of relative solvent accessibility (P = 0.2751)
MVP		0.95
MPC		2.4
ClinPred		1.0	D
GERP RS		2.8
Varity_R		0.87
gMVP		0.99
Mutation Taster		=17/83	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

Other links and lift over

dbSNP: rs137853021; hg19: chr2-45169582;