Variant 2-44942824-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_005413.4(SIX3):c.720G>T(p.Ala240Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,599,534 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 4 hom. )

Consequence

SIX3
NM_005413.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.472

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=-0.66).

BP6

Variant 2-44942824-G-T is Benign according to our data. Variant chr2-44942824-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 259762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-44942824-G-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.472 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00177 (270/152326) while in subpopulation NFE AF= 0.00178 (121/68028). AF 95% confidence interval is 0.00152. There are 0 homozygotes in gnomad4. There are 152 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 270 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIX3	NM_005413.4 linkuse as main transcript	c.720G>T	p.Ala240Ala	synonymous_variant	1/2	ENST00000260653.5	NP_005404.1	O95343

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIX3	ENST00000260653.5 linkuse as main transcript	c.720G>T	p.Ala240Ala	synonymous_variant	1/2	1	NM_005413.4	ENSP00000260653.3		O95343

Frequencies

GnomAD3 genomes

AF:

0.00177

AC:

270

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000313

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00951

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00178

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.00151

AC:

356

AN:

235808

Hom.:

AF XY:

0.00146

AC XY:

189

AN XY:

129350

show subpopulations

Gnomad AFR exome

AF:

0.000537

Gnomad AMR exome

AF:

0.000698

Gnomad ASJ exome

AF:

0.00111

Gnomad EAS exome

AF:

0.0000566

Gnomad SAS exome

AF:

0.000819

Gnomad FIN exome

AF:

0.00733

Gnomad NFE exome

AF:

0.00170

Gnomad OTH exome

AF:

0.00219

GnomAD4 exome

AF:

0.00178

AC:

2573

AN:

1447208

Hom.:

Cov.:

AF XY:

0.00177

AC XY:

1272

AN XY:

720334

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.000738

Gnomad4 ASJ exome

AF:

0.00115

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00102

Gnomad4 FIN exome

AF:

0.00626

Gnomad4 NFE exome

AF:

0.00186

Gnomad4 OTH exome

AF:

0.00141

GnomAD4 genome

AF:

0.00177

AC:

270

AN:

152326

Hom.:

Cov.:

AF XY:

0.00204

AC XY:

152

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.00176

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00951

Gnomad4 NFE

AF:

0.00178

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000934

Hom.:

Bravo

AF:

0.00114

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00147

EpiControl

AF:

0.00190

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 09, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Holoprosencephaly 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 20, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Benign

0.86

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