Genetic Variant SIX3:p.Gly57Cys (chr2-44942273-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_005413.4(SIX3):c.169G>T(p.Gly57Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000217 in 1,384,510 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G57D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

SIX3
NM_005413.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.76

Publications

1 publications found

Variant links:

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]

SIX3 links:

ENSG00000225156 (HGNC:):

ENSG00000225156 links:

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

SIX3-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3660761).

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.169G>T	p.Gly57Cys	missense	Exon 1 of 2	NP_005404.1	O95343

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SIX3	ENST00000260653.5	TSL:1 MANE Select	c.169G>T	p.Gly57Cys	missense	Exon 1 of 2	ENSP00000260653.3	O95343
ENSG00000225156	ENST00000760330.1		n.135+7897G>T		intron	N/A
SIX3-AS1	ENST00000760560.1		n.389-1440C>A		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

141678

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000217

AC:

AN:

1384510

Hom.:

Cov.:

AF XY:

0.00000439

AC XY:

AN XY:

683900

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31682

American (AMR)

AF:

0.00

AC:

AN:

36284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24008

East Asian (EAS)

AF:

0.0000544

AC:

AN:

36788

South Asian (SAS)

AF:

0.00

AC:

AN:

79002

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33974

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5232

European-Non Finnish (NFE)

AF:

9.26e-7

AC:

AN:

1079958

Other (OTH)

AF:

0.00

AC:

AN:

57582

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Holoprosencephaly 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

Eigen

Benign

0.019

Eigen_PC

Benign

0.012

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.53

M_CAP

Pathogenic

0.78

MetaRNN

Benign

0.37

MetaSVM

Uncertain

-0.089

MutationAssessor

Benign

0.0

PhyloP100

1.8

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

0.16

REVEL

Uncertain

0.34

Sift

Benign

0.041

Sift4G

Uncertain

0.0050

Polyphen

0.99

Vest4

0.27

MutPred

0.32

Loss of relative solvent accessibility (P = 0.0071)

MVP

0.99

MPC

1.1

ClinPred

0.34

GERP RS

2.7

Varity_R

0.13

gMVP

0.79

Mutation Taster

=32/68

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over