19-45765818-G-A

Variant names:

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.1903C>T(p.Pro635Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 1,602,080 control chromosomes in the GnomAD database, including 177,589 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.44 ( 15502 hom., cov: 32)

Exomes 𝑓: 0.47 ( 162087 hom. )

Consequence

SIX5
NM_175875.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.360

Publications

49 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.834061E-6).

BP6

Variant 19-45765818-G-A is Benign according to our data. Variant chr19-45765818-G-A is described in ClinVar as Benign. ClinVar VariationId is 262912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.623 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIX5	NM_175875.5 link	c.1903C>T	p.Pro635Ser	missense_variant	Exon 3 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.1903C>T	p.Pro635Ser	missense_variant	Exon 3 of 3	1	NM_175875.5	ENSP00000316842.4	Q8N196
ENSG00000259605	ENST00000559756.1 link	n.1034G>A		non_coding_transcript_exon_variant	Exon 1 of 2	3
SIX5	ENST00000560160.1 link	c.*113C>T		3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000453239.2	H0YLK1
SIX5	ENST00000560168.1 link	c.*1329C>T		3_prime_UTR_variant	Exon 3 of 3	4		ENSP00000453189.2	H0YLF6

Frequencies

GnomAD3 genomes

AF:

0.443

AC:

67261

AN:

151912

Hom.:

15488

Cov.:

show subpopulations

Gnomad AFR

AF:

0.347

Gnomad AMI

AF:

0.277

Gnomad AMR

AF:

0.567

Gnomad ASJ

AF:

0.370

Gnomad EAS

AF:

0.641

Gnomad SAS

AF:

0.586

Gnomad FIN

AF:

0.466

Gnomad MID

AF:

0.500

Gnomad NFE

AF:

0.450

Gnomad OTH

AF:

0.451

GnomAD2 exomes

AF:

0.506

AC:

119863

AN:

237074

AF XY:

0.503

show subpopulations

Gnomad AFR exome

AF:

0.344

Gnomad AMR exome

AF:

0.670

Gnomad ASJ exome

AF:

0.362

Gnomad EAS exome

AF:

0.628

Gnomad FIN exome

AF:

0.480

Gnomad NFE exome

AF:

0.451

Gnomad OTH exome

AF:

0.480

GnomAD4 exome

AF:

0.467

AC:

677894

AN:

1450050

Hom.:

162087

Cov.:

AF XY:

0.470

AC XY:

339330

AN XY:

721764

show subpopulations

African (AFR)

AF:

0.343

AC:

11468

AN:

33474

American (AMR)

AF:

0.657

AC:

29314

AN:

44640

Ashkenazi Jewish (ASJ)

AF:

0.369

AC:

9636

AN:

26110

East Asian (EAS)

AF:

0.665

AC:

26379

AN:

39686

South Asian (SAS)

AF:

0.581

AC:

50128

AN:

86242

European-Finnish (FIN)

AF:

0.476

AC:

20101

AN:

42216

Middle Eastern (MID)

AF:

0.444

AC:

2551

AN:

5746

European-Non Finnish (NFE)

AF:

0.450

AC:

500656

AN:

1111644

Other (OTH)

AF:

0.459

AC:

27661

AN:

60292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

24164

48327

72491

96654

120818

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15246

30492

45738

60984

76230

<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:

0.443

AC:

67303

AN:

152030

Hom.:

15502

Cov.:

AF XY:

0.451

AC XY:

33489

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.347

AC:

14396

AN:

41482

American (AMR)

AF:

0.568

AC:

8672

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.370

AC:

1285

AN:

3472

East Asian (EAS)

AF:

0.641

AC:

3304

AN:

5154

South Asian (SAS)

AF:

0.586

AC:

2820

AN:

4816

European-Finnish (FIN)

AF:

0.466

AC:

4923

AN:

10570

Middle Eastern (MID)

AF:

0.503

AC:

148

AN:

294

European-Non Finnish (NFE)

AF:

0.450

AC:

30543

AN:

67938

Other (OTH)

AF:

0.454

AC:

959

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1893

3786

5680

7573

9466

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

618

1236

1854

2472

3090

<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:

0.447

Hom.:

9863

Bravo

AF:

0.446

TwinsUK

AF:

0.441

AC:

1635

ALSPAC

AF:

0.455

AC:

1752

ESP6500AA

AF:

0.345

AC:

1510

ESP6500EA

AF:

0.433

AC:

3703

ExAC

AF:

0.493

AC:

59560

Asia WGS

AF:

0.586

AC:

2040

AN:

3478

EpiCase

AF:

0.442

EpiControl

AF:

0.440

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 09, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Branchiootorenal syndrome 2

Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.080

T;T;T

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.61

.;T;T

MetaRNN

Benign

0.0000078

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.69

N;N;.

PhyloP100

0.36

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.070

.;N;.

REVEL

Benign

0.14

Sift

Benign

0.35

.;T;.

Sift4G

Benign

0.70

.;T;D

Polyphen

0.0040

B;B;.

Vest4

0.057, 0.039

MPC

0.045

ClinPred

0.0043

GERP RS

-0.76

Varity_R

0.032

gMVP

0.18

Mutation Taster

=99/1

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over