2-44942213-G-T

Position:

chr2-44942213-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005413.4(SIX3):c.109G>T(p.Gly37Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00231 in 1,589,978 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0023 ( 11 hom. )

Consequence

SIX3
NM_005413.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:3B:7

Conservation

PhyloP100: -0.103

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010941207).

BP6

Variant 2-44942213-G-T is Benign according to our data. Variant chr2-44942213-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 30381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-44942213-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0021 (317/151256) while in subpopulation AMR AF= 0.00789 (120/15210). AF 95% confidence interval is 0.00674. There are 1 homozygotes in gnomad4. There are 177 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 317 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIX3	NM_005413.4 linkuse as main transcript	c.109G>T	p.Gly37Cys	missense_variant	1/2	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.109G>T	p.Gly37Cys	missense_variant	1/2	1	NM_005413.4	ENSP00000260653	P1

Frequencies

GnomAD3 genomes

AF:

0.00210

AC:

317

AN:

151146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000581

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00790

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00254

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00129

AC:

299

AN:

231504

Hom.:

AF XY:

0.00124

AC XY:

157

AN XY:

126974

show subpopulations

Gnomad AFR exome

AF:

0.000403

Gnomad AMR exome

AF:

0.00180

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000171

Gnomad NFE exome

AF:

0.00207

Gnomad OTH exome

AF:

0.00120

GnomAD4 exome

AF:

0.00233

AC:

3356

AN:

1438722

Hom.:

Cov.:

AF XY:

0.00227

AC XY:

1623

AN XY:

715778

show subpopulations

Gnomad4 AFR exome

AF:

0.000333

Gnomad4 AMR exome

AF:

0.00156

Gnomad4 ASJ exome

AF:

0.000193

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000258

Gnomad4 NFE exome

AF:

0.00284

Gnomad4 OTH exome

AF:

0.00191

GnomAD4 genome

AF:

0.00210

AC:

317

AN:

151256

Hom.:

Cov.:

AF XY:

0.00240

AC XY:

177

AN XY:

73892

show subpopulations

Gnomad4 AFR

AF:

0.000580

Gnomad4 AMR

AF:

0.00789

Gnomad4 ASJ

AF:

0.000289

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00254

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00208

Hom.:

Bravo

AF:

0.00216

ESP6500AA

AF:

0.000600

AC:

ESP6500EA

AF:

0.00246

AC:

ExAC

AF:

0.000940

AC:

111

EpiCase

AF:

0.00224

EpiControl

AF:

0.00167

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:3Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 12, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 11, 2019	This variant is associated with the following publications: (PMID: 18791198, 26080100, 20157829, 19346217) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	SIX3: BS1, BS2 -

Holoprosencephaly 2

Pathogenic:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 28, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2010	- -

Solitary median maxillary central incisor syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Center for Human Genetics, University of Leuven

- -

Schizencephaly

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2010

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 31, 2015

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

SIX3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 06, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.21

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.34

M_CAP

Pathogenic

0.73

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.44

REVEL

Uncertain

0.47

Sift

Benign

0.054

Sift4G

Pathogenic

0.0

Polyphen

0.0

Vest4

0.20

MVP

0.61

MPC

1.1

ClinPred

0.0068

GERP RS

-0.74

Varity_R

0.12

gMVP

0.72

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