Genetic Variant SIX3:c.-280_-275delCCTCTC (chr2-44941807-TCTCTCC-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBA1

The NM_005413.4(SIX3):c.-280_-275delCCTCTC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0563 in 360,230 control chromosomes in the GnomAD database, including 1,072 homozygotes. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.079 ( 728 hom., cov: 28)

Exomes 𝑓: 0.040 ( 344 hom. )

Consequence

SIX3
NM_005413.4 5_prime_UTR

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.734

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP6

Variant 2-44941807-TCTCTCC-T is Benign according to our data. Variant chr2-44941807-TCTCTCC-T is described in ClinVar as Benign. ClinVar VariationId is 1243127.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.158 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.-280_-275delCCTCTC		5_prime_UTR	Exon 1 of 2	NP_005404.1	O95343
	SIX3-AS1	NR_103786.1		n.66_71delGGAGAG		non_coding_transcript_exon	Exon 1 of 2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SIX3	ENST00000260653.5	TSL:1 MANE Select	c.-280_-275delCCTCTC	5_prime_UTR	Exon 1 of 2	ENSP00000260653.3	O95343
SIX3-AS1	ENST00000419364.4	TSL:2	n.256_261delGGAGAG	non_coding_transcript_exon	Exon 1 of 2
SIX3-AS1	ENST00000760562.1		n.19_24delGGAGAG	non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.0784

AC:

11866

AN:

151298

Hom.:

705

Cov.:

show subpopulations

Gnomad AFR

AF:

0.160

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0850

Gnomad ASJ

AF:

0.105

Gnomad EAS

AF:

0.0525

Gnomad SAS

AF:

0.0714

Gnomad FIN

AF:

0.0252

Gnomad MID

AF:

0.112

Gnomad NFE

AF:

0.0373

Gnomad OTH

AF:

0.0883

GnomAD4 exome

AF:

0.0399

AC:

8341

AN:

208812

Hom.:

344

AF XY:

0.0414

AC XY:

4563

AN XY:

110198

show subpopulations

African (AFR)

AF:

0.136

AC:

863

AN:

6328

American (AMR)

AF:

0.0763

AC:

770

AN:

10088

Ashkenazi Jewish (ASJ)

AF:

0.0781

AC:

443

AN:

5670

East Asian (EAS)

AF:

0.0354

AC:

427

AN:

12060

South Asian (SAS)

AF:

0.0594

AC:

1591

AN:

26790

European-Finnish (FIN)

AF:

0.0172

AC:

210

AN:

12196

Middle Eastern (MID)

AF:

0.0588

AC:

AN:

850

European-Non Finnish (NFE)

AF:

0.0281

AC:

3454

AN:

122980

Other (OTH)

AF:

0.0450

AC:

533

AN:

11850

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

373

746

1120

1493

1866

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<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:

0.0788

AC:

11929

AN:

151418

Hom.:

728

Cov.:

AF XY:

0.0782

AC XY:

5783

AN XY:

73998

show subpopulations

African (AFR)

AF:

0.161

AC:

6645

AN:

41170

American (AMR)

AF:

0.0853

AC:

1301

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.105

AC:

363

AN:

3468

East Asian (EAS)

AF:

0.0524

AC:

267

AN:

5092

South Asian (SAS)

AF:

0.0712

AC:

339

AN:

4758

European-Finnish (FIN)

AF:

0.0252

AC:

266

AN:

10570

Middle Eastern (MID)

AF:

0.110

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0373

AC:

2532

AN:

67814

Other (OTH)

AF:

0.0874

AC:

183

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

501

1003

1504

2006

2507

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

134

268

402

536

670

<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:

0.0147

Hom.:

Bravo

AF:

0.0893

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.73

Mutation Taster

=298/2

polymorphism (auto)

(source)

Splicing

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