19-45765644-C-T

Position:

chr19-45765644-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_175875.5(SIX5):c.2077G>A(p.Val693Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 1,612,970 control chromosomes in the GnomAD database, including 97,361 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.33 ( 8345 hom., cov: 33)

Exomes 𝑓: 0.35 ( 89016 hom. )

Consequence

SIX5
NM_175875.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.0790

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=0.0041387975).

BP6

Variant 19-45765644-C-T is Benign according to our data. Variant chr19-45765644-C-T is described in ClinVar as [Benign]. Clinvar id is 262913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-45765644-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.355 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.2077G>A	p.Val693Met	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.2077G>A	p.Val693Met	missense_variant	3/3	1	NM_175875.5	ENSP00000316842	P1
	ENST00000559756.1 linkuse as main transcript	n.860C>T		non_coding_transcript_exon_variant	1/2	3
SIX5	ENST00000560160.1 linkuse as main transcript	c.*287G>A		3_prime_UTR_variant	2/2	2		ENSP00000453239
SIX5	ENST00000560168.1 linkuse as main transcript	c.*1503G>A		3_prime_UTR_variant	3/3	4		ENSP00000453189

Frequencies

GnomAD3 genomes

AF:

0.329

AC:

49969

AN:

151972

Hom.:

8344

Cov.:

show subpopulations

Gnomad AFR

AF:

0.313

Gnomad AMI

AF:

0.314

Gnomad AMR

AF:

0.263

Gnomad ASJ

AF:

0.415

Gnomad EAS

AF:

0.266

Gnomad SAS

AF:

0.288

Gnomad FIN

AF:

0.319

Gnomad MID

AF:

0.332

Gnomad NFE

AF:

0.358

Gnomad OTH

AF:

0.319

GnomAD3 exomes

AF:

0.320

AC:

79957

AN:

250156

Hom.:

13482

AF XY:

0.323

AC XY:

43820

AN XY:

135532

show subpopulations

Gnomad AFR exome

AF:

0.314

Gnomad AMR exome

AF:

0.210

Gnomad ASJ exome

AF:

0.424

Gnomad EAS exome

AF:

0.284

Gnomad SAS exome

AF:

0.290

Gnomad FIN exome

AF:

0.319

Gnomad NFE exome

AF:

0.357

Gnomad OTH exome

AF:

0.338

GnomAD4 exome

AF:

0.345

AC:

504731

AN:

1460880

Hom.:

89016

Cov.:

AF XY:

0.345

AC XY:

251012

AN XY:

726800

show subpopulations

Gnomad4 AFR exome

AF:

0.308

Gnomad4 AMR exome

AF:

0.218

Gnomad4 ASJ exome

AF:

0.418

Gnomad4 EAS exome

AF:

0.218

Gnomad4 SAS exome

AF:

0.293

Gnomad4 FIN exome

AF:

0.314

Gnomad4 NFE exome

AF:

0.360

Gnomad4 OTH exome

AF:

0.350

GnomAD4 genome

AF:

0.329

AC:

49984

AN:

152090

Hom.:

8345

Cov.:

AF XY:

0.323

AC XY:

24007

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.313

Gnomad4 AMR

AF:

0.262

Gnomad4 ASJ

AF:

0.415

Gnomad4 EAS

AF:

0.266

Gnomad4 SAS

AF:

0.289

Gnomad4 FIN

AF:

0.319

Gnomad4 NFE

AF:

0.358

Gnomad4 OTH

AF:

0.316

Alfa

AF:

0.344

Hom.:

6193

Bravo

AF:

0.323

TwinsUK

AF:

0.362

AC:

1341

ALSPAC

AF:

0.352

AC:

1355

ESP6500AA

AF:

0.305

AC:

1342

ESP6500EA

AF:

0.364

AC:

3127

ExAC

AF:

0.319

AC:

38720

Asia WGS

AF:

0.285

AC:

991

AN:

3478

EpiCase

AF:

0.371

EpiControl

AF:

0.375

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Branchiootorenal syndrome 2

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -

not provided

Benign:2

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

T;T;T

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.81

.;T;T

MetaRNN

Benign

0.0041

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;N;.

MutationTaster

Benign

1.0

P;P

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.27

.;N;.

REVEL

Benign

0.23

Sift

Benign

0.032

.;D;.

Sift4G

Benign

0.10

.;T;T

Polyphen

0.63

P;P;.

Vest4

0.27, 0.068

MPC

0.13

ClinPred

0.018

GERP RS

3.1

Varity_R

0.083

gMVP

0.067

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