rs2014576

Positions:

chr19-45765818-G-A

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

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

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 262912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-45765818-G-A is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
SIX5	NM_175875.5 linkuse as main transcript	c.1903C>T	p.Pro635Ser	missense_variant	3/3	ENST00000317578.7	NP_787071.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
SIX5	ENST00000317578.7 linkuse as main transcript	c.1903C>T	p.Pro635Ser	missense_variant	3/3	1	NM_175875.5	ENSP00000316842	P1
	ENST00000559756.1 linkuse as main transcript	n.1034G>A		non_coding_transcript_exon_variant	1/2	3
SIX5	ENST00000560160.1 linkuse as main transcript	c.*113C>T		3_prime_UTR_variant	2/2	2		ENSP00000453239
SIX5	ENST00000560168.1 linkuse as main transcript	c.*1329C>T		3_prime_UTR_variant	3/3	4		ENSP00000453189

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

GnomAD3 exomes

AF:

0.506

AC:

119863

AN:

237074

Hom.:

31561

AF XY:

0.503

AC XY:

65396

AN XY:

130078

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 SAS exome

AF:

0.585

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

Gnomad4 AFR exome

AF:

0.343

Gnomad4 AMR exome

AF:

0.657

Gnomad4 ASJ exome

AF:

0.369

Gnomad4 EAS exome

AF:

0.665

Gnomad4 SAS exome

AF:

0.581

Gnomad4 FIN exome

AF:

0.476

Gnomad4 NFE exome

AF:

0.450

Gnomad4 OTH exome

AF:

0.459

GnomAD4 genome

AF:

0.443

AC:

67303

AN:

152030

Hom.:

15502

Cov.:

AF XY:

0.451

AC XY:

33489

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.347

Gnomad4 AMR

AF:

0.568

Gnomad4 ASJ

AF:

0.370

Gnomad4 EAS

AF:

0.641

Gnomad4 SAS

AF:

0.586

Gnomad4 FIN

AF:

0.466

Gnomad4 NFE

AF:

0.450

Gnomad4 OTH

AF:

0.454

Alfa

AF:

0.441

Hom.:

5942

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

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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. -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Branchiootorenal syndrome 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

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

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;.

MutationTaster

Benign

1.0

P;P

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over