dbSNP rs3745802: SIX5:c.803+123C>A (chr19-45767919-G-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_175875.5(SIX5):c.803+123C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.475 in 1,052,008 control chromosomes in the GnomAD database, including 121,433 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.47 ( 17269 hom., cov: 34)

Exomes 𝑓: 0.48 ( 104164 hom. )

Consequence

SIX5
NM_175875.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.277

Publications

9 publications found

Variant links:

Genes affected

SIX5 (HGNC:10891): (SIX homeobox 5) The protein encoded by this gene is a homeodomain-containing transcription factor that appears to function in the regulation of organogenesis. This gene is located downstream of the dystrophia myotonica-protein kinase gene. Mutations in this gene are a cause of branchiootorenal syndrome type 2. [provided by RefSeq, Jul 2009]

SIX5 links:

DM1-AS (HGNC:53125): (DM1 locus antisense RNA)

DM1-AS links:

ENSG00000259605 (HGNC:):

ENSG00000259605 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 19-45767919-G-T is Benign according to our data. Variant chr19-45767919-G-T is described in ClinVar as Benign. ClinVar VariationId is 1174287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.624 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175875.5. 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
	SIX5	NM_175875.5	MANE Select	c.803+123C>A		intron	N/A	NP_787071.3
	DM1-AS	NR_147193.1		n.124G>T		non_coding_transcript_exon	Exon 1 of 2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SIX5	ENST00000317578.7	TSL:1 MANE Select	c.803+123C>A	intron	N/A	ENSP00000316842.4	Q8N196
SIX5	ENST00000560160.1	TSL:2	c.584+123C>A	intron	N/A	ENSP00000453239.2	H0YLK1
SIX5	ENST00000560168.1	TSL:4	c.201+123C>A	intron	N/A	ENSP00000453189.2	H0YLF6

Frequencies

GnomAD3 genomes

AF:

0.471

AC:

71630

AN:

151956

Hom.:

17255

Cov.:

show subpopulations

Gnomad AFR

AF:

0.423

Gnomad AMI

AF:

0.291

Gnomad AMR

AF:

0.591

Gnomad ASJ

AF:

0.391

Gnomad EAS

AF:

0.642

Gnomad SAS

AF:

0.595

Gnomad FIN

AF:

0.457

Gnomad MID

AF:

0.525

Gnomad NFE

AF:

0.460

Gnomad OTH

AF:

0.481

GnomAD4 exome

AF:

0.475

AC:

427807

AN:

899934

Hom.:

104164

Cov.:

AF XY:

0.479

AC XY:

215279

AN XY:

449638

show subpopulations

African (AFR)

AF:

0.417

AC:

8543

AN:

20502

American (AMR)

AF:

0.641

AC:

13297

AN:

20752

Ashkenazi Jewish (ASJ)

AF:

0.386

AC:

6596

AN:

17076

East Asian (EAS)

AF:

0.667

AC:

21883

AN:

32828

South Asian (SAS)

AF:

0.588

AC:

33162

AN:

56394

European-Finnish (FIN)

AF:

0.472

AC:

14262

AN:

30188

Middle Eastern (MID)

AF:

0.472

AC:

1369

AN:

2898

European-Non Finnish (NFE)

AF:

0.456

AC:

309225

AN:

678414

Other (OTH)

AF:

0.476

AC:

19470

AN:

40882

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

11632

23265

34897

46530

58162

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8160

16320

24480

32640

40800

<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:

0.471

AC:

71684

AN:

152074

Hom.:

17269

Cov.:

AF XY:

0.478

AC XY:

35528

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.423

AC:

17572

AN:

41542

American (AMR)

AF:

0.592

AC:

9053

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.391

AC:

1356

AN:

3470

East Asian (EAS)

AF:

0.642

AC:

3287

AN:

5116

South Asian (SAS)

AF:

0.595

AC:

2867

AN:

4822

European-Finnish (FIN)

AF:

0.457

AC:

4839

AN:

10588

Middle Eastern (MID)

AF:

0.531

AC:

156

AN:

294

European-Non Finnish (NFE)

AF:

0.460

AC:

31269

AN:

67932

Other (OTH)

AF:

0.484

AC:

1020

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1977

3954

5932

7909

9886

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

650

1300

1950

2600

3250

<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:

0.479

Hom.:

7467

Bravo

AF:

0.480

Asia WGS

AF:

0.595

AC:

2071

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

9.2

(source)

DANN

Benign

0.79

PhyloP100

0.28

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