chr2-44942824-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_005413.4(SIX3):c.720G>T(p.Ala240Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,599,534 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 4 hom. )

Consequence

SIX3
NM_005413.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.472

Publications

4 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:

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=-0.66).

BP6

Variant 2-44942824-G-T is Benign according to our data. Variant chr2-44942824-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.472 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00177 (270/152326) while in subpopulation NFE AF = 0.00178 (121/68028). AF 95% confidence interval is 0.00152. There are 0 homozygotes in GnomAd4. There are 152 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIX3	NM_005413.4 link	c.720G>T	p.Ala240Ala	synonymous_variant	Exon 1 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.720G>T	p.Ala240Ala	synonymous_variant	Exon 1 of 2	1	NM_005413.4	ENSP00000260653.3	O95343
ENSG00000225156	ENST00000760330.1 link	n.135+8448G>T		intron_variant	Intron 1 of 1
SIX3-AS1	ENST00000760560.1 link	n.389-1991C>A		intron_variant	Intron 1 of 1
SIX3-AS1	ENST00000760561.1 link	n.365+1563C>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.00177

AC:

270

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000313

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00951

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00178

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00151

AC:

356

AN:

235808

AF XY:

0.00146

show subpopulations

Gnomad AFR exome

AF:

0.000537

Gnomad AMR exome

AF:

0.000698

Gnomad ASJ exome

AF:

0.00111

Gnomad EAS exome

AF:

0.0000566

Gnomad FIN exome

AF:

0.00733

Gnomad NFE exome

AF:

0.00170

Gnomad OTH exome

AF:

0.00219

GnomAD4 exome

AF:

0.00178

AC:

2573

AN:

1447208

Hom.:

Cov.:

AF XY:

0.00177

AC XY:

1272

AN XY:

720334

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33474

American (AMR)

AF:

0.000738

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

26130

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39692

South Asian (SAS)

AF:

0.00102

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00626

AC:

244

AN:

38974

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00186

AC:

2071

AN:

1111896

Other (OTH)

AF:

0.00141

AC:

AN:

60300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

165

331

496

662

827

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

156

234

312

390

<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:

0.00177

AC:

270

AN:

152326

Hom.:

Cov.:

AF XY:

0.00204

AC XY:

152

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41590

American (AMR)

AF:

0.00176

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5170

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00951

AC:

101

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00178

AC:

121

AN:

68028

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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:

0.000934

Hom.:

Bravo

AF:

0.00114

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00147

EpiControl

AF:

0.00190

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 09, 2016

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Holoprosencephaly 2

Benign:1

Jan 22, 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

-0.66

CADD

Benign

(source)

DANN

Benign

0.86

PhyloP100

0.47

Mutation Taster

=94/6

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over