rs121917879

Variant names:

• chr2-44942874-G-C
• rs121917879
• NM_005413.4:c.770G>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_005413.4(SIX3):​c.770G>C​(p.Arg257Pro) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R257G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SIX3 NM_005413.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 9.66
• Publications: 9 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_005413.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 2-44942874-G-C is Pathogenic according to our data. Variant chr2-44942874-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 6094.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.770G>C	p.Arg257Pro	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.770G>C	p.Arg257Pro	missense	Exon 1 of 2	ENSP00000260653.3	O95343
	ENSG00000225156	ENST00000760330.1		n.135+8498G>C		intron	N/A
	SIX3-AS1	ENST00000760560.1		n.389-2041C>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
3	-	-	Holoprosencephaly 2 (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	35
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H
PhyloP100		9.7
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.040	D
Polyphen		0.97	D
Vest4		0.98
MutPred		0.91		Gain of glycosylation at R257 (P = 0.0354)
MVP		1.0
MPC		2.5
ClinPred		1.0	D
GERP RS		2.4
Varity_R		0.99
gMVP		1.0
Mutation Taster		=24/76	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: rs121917879; hg19: chr2-45170013;