Genetic Variant SIX3:p.Ala30Ala (chr2-44942194-G-T) – ACMG Classification: Benign (-21 pts)

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.90G>T(p.Ala30Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0193 in 1,596,786 control chromosomes in the GnomAD database, including 678 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 64 hom., cov: 31)

Exomes 𝑓: 0.019 ( 614 hom. )

Consequence

SIX3
NM_005413.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.52

Publications

6 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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant 2-44942194-G-T is Benign according to our data. Variant chr2-44942194-G-T is described in ClinVar as Benign. ClinVar VariationId is 65505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.52 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0544 is higher than 0.05.

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.90G>T	p.Ala30Ala	synonymous	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.90G>T	p.Ala30Ala	synonymous	Exon 1 of 2	ENSP00000260653.3	O95343
ENSG00000225156	ENST00000760330.1		n.135+7818G>T		intron	N/A
SIX3-AS1	ENST00000760560.1		n.389-1361C>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0205

AC:

3103

AN:

151380

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00918

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0574

Gnomad ASJ

AF:

0.0689

Gnomad EAS

AF:

0.0498

Gnomad SAS

AF:

0.0438

Gnomad FIN

AF:

0.0102

Gnomad MID

AF:

0.0796

Gnomad NFE

AF:

0.0138

Gnomad OTH

AF:

0.0385

GnomAD2 exomes

AF:

0.0354

AC:

8294

AN:

234134

AF XY:

0.0338

show subpopulations

Gnomad AFR exome

AF:

0.00948

Gnomad AMR exome

AF:

0.0932

Gnomad ASJ exome

AF:

0.0734

Gnomad EAS exome

AF:

0.0529

Gnomad FIN exome

AF:

0.00882

Gnomad NFE exome

AF:

0.0148

Gnomad OTH exome

AF:

0.0346

GnomAD4 exome

AF:

0.0191

AC:

27641

AN:

1445294

Hom.:

614

Cov.:

AF XY:

0.0200

AC XY:

14403

AN XY:

719418

show subpopulations

African (AFR)

AF:

0.00854

AC:

285

AN:

33372

American (AMR)

AF:

0.0894

AC:

3991

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.0765

AC:

1994

AN:

26054

East Asian (EAS)

AF:

0.0380

AC:

1502

AN:

39574

South Asian (SAS)

AF:

0.0457

AC:

3941

AN:

86178

European-Finnish (FIN)

AF:

0.00739

AC:

289

AN:

39092

Middle Eastern (MID)

AF:

0.0590

AC:

317

AN:

5376

European-Non Finnish (NFE)

AF:

0.0124

AC:

13828

AN:

1110880

Other (OTH)

AF:

0.0249

AC:

1494

AN:

60102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1541

3081

4622

6162

7703

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

606

1212

1818

2424

3030

<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:

0.0205

AC:

3105

AN:

151492

Hom.:

Cov.:

AF XY:

0.0217

AC XY:

1604

AN XY:

73990

show subpopulations

African (AFR)

AF:

0.00922

AC:

382

AN:

41420

American (AMR)

AF:

0.0576

AC:

877

AN:

15238

Ashkenazi Jewish (ASJ)

AF:

0.0689

AC:

238

AN:

3456

East Asian (EAS)

AF:

0.0498

AC:

256

AN:

5144

South Asian (SAS)

AF:

0.0438

AC:

210

AN:

4792

European-Finnish (FIN)

AF:

0.0102

AC:

106

AN:

10402

Middle Eastern (MID)

AF:

0.0753

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0138

AC:

933

AN:

67736

Other (OTH)

AF:

0.0381

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

144

288

431

575

719

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0154

Hom.:

Bravo

AF:

0.0264

Asia WGS

AF:

0.0320

AC:

110

AN:

3478

EpiCase

AF:

0.0195

EpiControl

AF:

0.0212

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Holoprosencephaly 2 (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.96

PhyloP100

1.5

PromoterAI

-0.049

Neutral

(source)

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over