Variant 2-44944703-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_005413.4(SIX3):c.942A>G(p.Ala314=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.926 in 1,586,652 control chromosomes in the GnomAD database, including 680,806 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.94 ( 66957 hom., cov: 30)

Exomes 𝑓: 0.92 ( 613849 hom. )

Consequence

SIX3
NM_005413.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.128

Variant links:

Genes affected

SIX3 (HGNC:10889): (SIX homeobox 3) This gene encodes a member of the sine oculis homeobox transcription factor family. The encoded protein plays a role in eye development. Mutations in this gene have been associated with holoprosencephaly type 2. [provided by RefSeq, Oct 2009]

SIX3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant 2-44944703-A-G is Benign according to our data. Variant chr2-44944703-A-G is described in ClinVar as [Benign]. Clinvar id is 167690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-44944703-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.128 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.966 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIX3	NM_005413.4 linkuse as main transcript	c.942A>G	p.Ala314=	synonymous_variant	2/2	ENST00000260653.5	NP_005404.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIX3	ENST00000260653.5 linkuse as main transcript	c.942A>G	p.Ala314=	synonymous_variant	2/2	1	NM_005413.4	ENSP00000260653	P1

Frequencies

GnomAD3 genomes

AF:

0.938

AC:

142500

AN:

151960

Hom.:

66913

Cov.:

show subpopulations

Gnomad AFR

AF:

0.974

Gnomad AMI

AF:

0.959

Gnomad AMR

AF:

0.925

Gnomad ASJ

AF:

0.922

Gnomad EAS

AF:

0.984

Gnomad SAS

AF:

0.881

Gnomad FIN

AF:

0.924

Gnomad MID

AF:

0.939

Gnomad NFE

AF:

0.922

Gnomad OTH

AF:

0.933

GnomAD3 exomes

AF:

0.925

AC:

197167

AN:

213246

Hom.:

91274

AF XY:

0.921

AC XY:

107789

AN XY:

117068

show subpopulations

Gnomad AFR exome

AF:

0.973

Gnomad AMR exome

AF:

0.931

Gnomad ASJ exome

AF:

0.925

Gnomad EAS exome

AF:

0.984

Gnomad SAS exome

AF:

0.881

Gnomad FIN exome

AF:

0.919

Gnomad NFE exome

AF:

0.920

Gnomad OTH exome

AF:

0.922

GnomAD4 exome

AF:

0.925

AC:

1326848

AN:

1434578

Hom.:

613849

Cov.:

AF XY:

0.924

AC XY:

658339

AN XY:

712870

show subpopulations

Gnomad4 AFR exome

AF:

0.973

Gnomad4 AMR exome

AF:

0.933

Gnomad4 ASJ exome

AF:

0.926

Gnomad4 EAS exome

AF:

0.978

Gnomad4 SAS exome

AF:

0.886

Gnomad4 FIN exome

AF:

0.920

Gnomad4 NFE exome

AF:

0.924

Gnomad4 OTH exome

AF:

0.928

GnomAD4 genome

AF:

0.938

AC:

142600

AN:

152074

Hom.:

66957

Cov.:

AF XY:

0.936

AC XY:

69587

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.974

Gnomad4 AMR

AF:

0.925

Gnomad4 ASJ

AF:

0.922

Gnomad4 EAS

AF:

0.984

Gnomad4 SAS

AF:

0.881

Gnomad4 FIN

AF:

0.924

Gnomad4 NFE

AF:

0.922

Gnomad4 OTH

AF:

0.932

Alfa

AF:

0.926

Hom.:

79366

Bravo

AF:

0.942

Asia WGS

AF:

0.911

AC:

3163

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 07, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 32022405) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -

Holoprosencephaly 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.69

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