Genetic Variant SIX3:p.Ile275Thr (chr2-44944585-T-C) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_005413.4(SIX3):c.824T>C(p.Ile275Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000462 in 1,578,884 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00046 ( 0 hom. )

Consequence

SIX3
NM_005413.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 5.56

Publications

0 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:

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

SIX3-AS1 links:

ENSG00000225156 (HGNC:):

ENSG00000225156 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.018870056).

BP6

Variant 2-44944585-T-C is Benign according to our data. Variant chr2-44944585-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 445995.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000453 (69/152270) while in subpopulation NFE AF = 0.000897 (61/68008). AF 95% confidence interval is 0.000716. There are 0 homozygotes in GnomAd4. There are 24 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIX3	NM_005413.4	MANE Select	c.824T>C	p.Ile275Thr	missense	Exon 2 of 2	NP_005404.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SIX3	ENST00000260653.5	TSL:1 MANE Select	c.824T>C	p.Ile275Thr	missense	Exon 2 of 2	ENSP00000260653.3
SIX3-AS1	ENST00000760561.1		n.167A>G		non_coding_transcript_exon	Exon 1 of 2
ENSG00000225156	ENST00000760330.1		n.135+10209T>C		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000453

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000897

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000344

AC:

AN:

194860

AF XY:

0.000286

show subpopulations

Gnomad AFR exome

AF:

0.000283

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000480

Gnomad NFE exome

AF:

0.000684

Gnomad OTH exome

AF:

0.000194

GnomAD4 exome

AF:

0.000463

AC:

660

AN:

1426614

Hom.:

Cov.:

AF XY:

0.000399

AC XY:

283

AN XY:

708534

show subpopulations

African (AFR)

AF:

0.000153

AC:

AN:

32776

American (AMR)

AF:

0.0000231

AC:

AN:

43258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25744

East Asian (EAS)

AF:

0.00

AC:

AN:

38232

South Asian (SAS)

AF:

0.0000119

AC:

AN:

83800

European-Finnish (FIN)

AF:

0.000492

AC:

AN:

36566

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5558

European-Non Finnish (NFE)

AF:

0.000560

AC:

617

AN:

1101376

Other (OTH)

AF:

0.000304

AC:

AN:

59304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

127

170

212

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000453

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41578

American (AMR)

AF:

0.0000654

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000897

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000427

Hom.:

Bravo

AF:

0.000446

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000546

AC:

ExAC

AF:

0.000354

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Holoprosencephaly 2 (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.21

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.56

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.85

M_CAP

Pathogenic

0.70

MetaRNN

Benign

0.019

MetaSVM

Benign

-0.48

MutationAssessor

Benign

0.55

PhyloP100

5.6

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-0.85

REVEL

Uncertain

0.35

Sift

Benign

0.064

Sift4G

Benign

0.20

Polyphen

0.0060

Vest4

0.32

MVP

0.70

MPC

1.3

ClinPred

0.016

GERP RS

1.3

Varity_R

0.15

gMVP

0.48

Mutation Taster

=73/27

polymorphism

(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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over