19-45766866-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP5BP4BS2

The NM_175875.5(SIX5):c.1093G>A(p.Gly365Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000388 in 1,544,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

SIX5
NM_175875.5 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1O:1

Conservation

PhyloP100: 0.465

Publications

5 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 Gene-Disease associations (from GenCC):

branchiootorenal syndrome 2
Inheritance: AD, Unknown Classification: DEFINITIVE, LIMITED Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
branchio-oto-renal syndrome
Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, ClinGen

SIX5 links:

ENSG00000259605 (HGNC:):

ENSG00000259605 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PP5

Variant 19-45766866-C-T is Pathogenic according to our data. Variant chr19-45766866-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 8600.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.34370086). . Strength limited to SUPPORTING due to the PP5.

BS2

High AC in GnomAdExome4 at 5 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIX5	NM_175875.5 link	c.1093G>A	p.Gly365Arg	missense_variant	Exon 2 of 3	ENST00000317578.7	NP_787071.3	Q8N196

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SIX5	ENST00000317578.7 link	c.1093G>A	p.Gly365Arg	missense_variant	Exon 2 of 3	1	NM_175875.5	ENSP00000316842.4	Q8N196
SIX5	ENST00000560168.1 link	c.*281G>A		3_prime_UTR_variant	Exon 3 of 3	4		ENSP00000453189.2	H0YLF6
SIX5	ENST00000560160.1 link	c.585-755G>A		intron_variant	Intron 1 of 1	2		ENSP00000453239.2	H0YLK1
ENSG00000259605	ENST00000559756.1 link	n.1180+902C>T		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000140

AC:

AN:

143016

AF XY:

0.0000129

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000892

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000185

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000359

AC:

AN:

1392246

Hom.:

Cov.:

AF XY:

0.00000291

AC XY:

AN XY:

686998

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31622

American (AMR)

AF:

0.00

AC:

AN:

36228

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25102

East Asian (EAS)

AF:

0.00

AC:

AN:

35900

South Asian (SAS)

AF:

0.00

AC:

AN:

79592

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41700

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4714

European-Non Finnish (NFE)

AF:

0.00000371

AC:

AN:

1079606

Other (OTH)

AF:

0.0000173

AC:

AN:

57782

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41574

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67998

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000178

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Branchiootorenal syndrome 2

Pathogenic:1Other:1

Apr 01, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

T;T

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.047

LIST_S2

Benign

0.67

.;T

M_CAP

Pathogenic

0.32

MetaRNN

Benign

0.34

T;T

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

0.55

N;N

PhyloP100

0.47

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.96

.;N

REVEL

Uncertain

0.57

Sift

Uncertain

0.0010

.;D

Sift4G

Benign

0.18

.;T

Polyphen

0.94

P;P

Vest4

0.81

MutPred

0.42

Gain of solvent accessibility (P = 0.006);Gain of solvent accessibility (P = 0.006);

MVP

0.79

MPC

0.17

ClinPred

0.13

GERP RS

0.52

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.16

gMVP

0.32

Mutation Taster

=95/5

disease causing (ClinVar)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over