chr2-44944703-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_005413.4(SIX3):c.942A>G(p.Ala314Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.926 in 1,586,652 control chromosomes in the GnomAD database, including 680,806 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.94 ( 66957 hom., cov: 30)

Exomes 𝑓: 0.92 ( 613849 hom. )

Consequence

SIX3
NM_005413.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.128

Publications

20 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant 2-44944703-A-G is Benign according to our data. Variant chr2-44944703-A-G is described in ClinVar as Benign. ClinVar VariationId is 167690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.128 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.966 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIX3	NM_005413.4 link	c.942A>G	p.Ala314Ala	synonymous_variant	Exon 2 of 2	ENST00000260653.5	NP_005404.1	O95343

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SIX3	ENST00000260653.5 link	c.942A>G	p.Ala314Ala	synonymous_variant	Exon 2 of 2	1	NM_005413.4	ENSP00000260653.3	O95343
SIX3-AS1	ENST00000760561.1 link	n.49T>C		non_coding_transcript_exon_variant	Exon 1 of 2
ENSG00000225156	ENST00000760330.1 link	n.135+10327A>G		intron_variant	Intron 1 of 1
SIX3-AS1	ENST00000760560.1 link	n.388+695T>C		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.938

AC:

142500

AN:

151960

Hom.:

66913

Cov.:

show subpopulations

Gnomad AFR

AF:

0.974

Gnomad AMI

AF:

0.959

Gnomad AMR

AF:

0.925

Gnomad ASJ

AF:

0.922

Gnomad EAS

AF:

0.984

Gnomad SAS

AF:

0.881

Gnomad FIN

AF:

0.924

Gnomad MID

AF:

0.939

Gnomad NFE

AF:

0.922

Gnomad OTH

AF:

0.933

GnomAD2 exomes

AF:

0.925

AC:

197167

AN:

213246

AF XY:

0.921

show subpopulations

Gnomad AFR exome

AF:

0.973

Gnomad AMR exome

AF:

0.931

Gnomad ASJ exome

AF:

0.925

Gnomad EAS exome

AF:

0.984

Gnomad FIN exome

AF:

0.919

Gnomad NFE exome

AF:

0.920

Gnomad OTH exome

AF:

0.922

GnomAD4 exome

AF:

0.925

AC:

1326848

AN:

1434578

Hom.:

613849

Cov.:

AF XY:

0.924

AC XY:

658339

AN XY:

712870

show subpopulations

African (AFR)

AF:

0.973

AC:

32205

AN:

33090

American (AMR)

AF:

0.933

AC:

40456

AN:

43368

Ashkenazi Jewish (ASJ)

AF:

0.926

AC:

23977

AN:

25884

East Asian (EAS)

AF:

0.978

AC:

37951

AN:

38786

South Asian (SAS)

AF:

0.886

AC:

74616

AN:

84252

European-Finnish (FIN)

AF:

0.920

AC:

34681

AN:

37708

Middle Eastern (MID)

AF:

0.919

AC:

5283

AN:

5748

European-Non Finnish (NFE)

AF:

0.924

AC:

1022208

AN:

1105994

Other (OTH)

AF:

0.928

AC:

55471

AN:

59748

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

6058

12116

18174

24232

30290

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21460

42920

64380

85840

107300

<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:

0.938

AC:

142600

AN:

152074

Hom.:

66957

Cov.:

AF XY:

0.936

AC XY:

69587

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.974

AC:

40422

AN:

41500

American (AMR)

AF:

0.925

AC:

14151

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.922

AC:

3199

AN:

3470

East Asian (EAS)

AF:

0.984

AC:

5041

AN:

5124

South Asian (SAS)

AF:

0.881

AC:

4218

AN:

4788

European-Finnish (FIN)

AF:

0.924

AC:

9808

AN:

10616

Middle Eastern (MID)

AF:

0.932

AC:

272

AN:

292

European-Non Finnish (NFE)

AF:

0.922

AC:

62642

AN:

67954

Other (OTH)

AF:

0.932

AC:

1972

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

443

885

1328

1770

2213

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

906

1812

2718

3624

4530

<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:

0.929

Hom.:

120612

Bravo

AF:

0.942

Asia WGS

AF:

0.911

AC:

3163

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Jul 07, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:4

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 32022405) -

Apr 20, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Holoprosencephaly 2

Benign:2

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.69

PhyloP100

0.13

Mutation Taster

=99/1

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over