dbSNP rs150550985: SIX1:p.Ala54Ala (chr14-60649028-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_005982.4(SIX1):c.162G>A(p.Ala54Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000248 in 1,613,950 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 0.00035 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 3 hom. )

Consequence

SIX1
NM_005982.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.130

Publications

1 publications found

Variant links:

Genes affected

SIX1 (HGNC:10887): (SIX homeobox 1) The protein encoded by this gene is a homeobox protein that is similar to the Drosophila 'sine oculis' gene product. This gene is found in a cluster of related genes on chromosome 14 and is thought to be involved in limb development. Defects in this gene are a cause of autosomal dominant deafness type 23 (DFNA23) and branchiootic syndrome type 3 (BOS3). [provided by RefSeq, Jul 2008]

SIX1 Gene-Disease associations (from GenCC):

autosomal dominant nonsyndromic hearing loss 23
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P
branchio-oto-renal syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, Ambry Genetics
branchiootic syndrome 3
Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
autosomal dominant nonsyndromic hearing loss
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
branchiootic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SIX1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.35).

BP6

Variant 14-60649028-C-T is Benign according to our data. Variant chr14-60649028-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.13 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000348 (53/152318) while in subpopulation AMR AF = 0.00118 (18/15300). AF 95% confidence interval is 0.00076. There are 1 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 53 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005982.4. 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
	SIX1	NM_005982.4	MANE Select	c.162G>A	p.Ala54Ala	synonymous	Exon 1 of 2	NP_005973.1	Q15475
	SIX1	NM_001425142.1		c.162G>A	p.Ala54Ala	synonymous	Exon 1 of 2	NP_001412071.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SIX1	ENST00000645694.3	MANE Select	c.162G>A	p.Ala54Ala	synonymous	Exon 1 of 2	ENSP00000494686.1	Q15475
SIX1	ENST00000949515.1		c.162G>A	p.Ala54Ala	synonymous	Exon 1 of 2	ENSP00000619574.1
SIX1	ENST00000554986.2	TSL:3	c.42-2451G>A		intron	N/A	ENSP00000452700.2	H0YK85

Frequencies

GnomAD3 genomes

AF:

0.000348

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000311

AC:

AN:

251066

AF XY:

0.000331

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00104

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000238

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.000237

AC:

347

AN:

1461632

Hom.:

Cov.:

AF XY:

0.000248

AC XY:

180

AN XY:

727118

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33480

American (AMR)

AF:

0.000961

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000128

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53216

Middle Eastern (MID)

AF:

0.0139

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.000161

AC:

179

AN:

1111986

Other (OTH)

AF:

0.000397

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.543

Heterozygous variant carriers

112

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.000348

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41582

American (AMR)

AF:

0.00118

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000415

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000294

AC:

AN:

68026

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

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:

0.000311

Hom.:

Bravo

AF:

0.000457

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000709

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Autosomal dominant nonsyndromic hearing loss 23 (1)

Branchiootic syndrome 3 (1)

Branchiootic syndrome 3;C1854594:Autosomal dominant nonsyndromic hearing loss 23 (1)

Branchiootic syndrome 3;C1854594:Autosomal dominant nonsyndromic hearing loss 23;C4551702:Branchiootorenal syndrome 1 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Benign

0.93

PhyloP100

-0.13

PromoterAI

-0.088

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over