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GeneBe

2-44942194-G-T

Variant summary

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

The NM_005413.4(SIX3):c.90G>T(p.Ala30=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0193 in 1,596,786 control chromosomes in the GnomAD database, including 678 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 64 hom., cov: 31)
Exomes 𝑓: 0.019 ( 614 hom. )

Consequence

SIX3
NM_005413.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.52
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.5).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 2-44942194-G-T is Benign according to our data. Variant chr2-44942194-G-T is described in ClinVar as [Benign]. Clinvar id is 65505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=1.52 with no splicing effect.
BA1
?
    BA1 - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0544 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SIX3NM_005413.4 linkuse as main transcriptc.90G>T p.Ala30= synonymous_variant 1/2 ENST00000260653.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SIX3ENST00000260653.5 linkuse as main transcriptc.90G>T p.Ala30= synonymous_variant 1/21 NM_005413.4 P1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0205
AC:
3103
AN:
151380
Hom.:
64
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00918
Gnomad AMI
AF:
0.00110
Gnomad AMR
AF:
0.0574
Gnomad ASJ
AF:
0.0689
Gnomad EAS
AF:
0.0498
Gnomad SAS
AF:
0.0438
Gnomad FIN
AF:
0.0102
Gnomad MID
AF:
0.0796
Gnomad NFE
AF:
0.0138
Gnomad OTH
AF:
0.0385
GnomAD3 exomes
AF:
0.0354
AC:
8294
AN:
234134
Hom.:
304
AF XY:
0.0338
AC XY:
4338
AN XY:
128228
show subpopulations
Gnomad AFR exome
AF:
0.00948
Gnomad AMR exome
AF:
0.0932
Gnomad ASJ exome
AF:
0.0734
Gnomad EAS exome
AF:
0.0529
Gnomad SAS exome
AF:
0.0447
Gnomad FIN exome
AF:
0.00882
Gnomad NFE exome
AF:
0.0148
Gnomad OTH exome
AF:
0.0346
GnomAD4 exome
AF:
0.0191
AC:
27641
AN:
1445294
Hom.:
614
Cov.:
32
AF XY:
0.0200
AC XY:
14403
AN XY:
719418
show subpopulations
Gnomad4 AFR exome
AF:
0.00854
Gnomad4 AMR exome
AF:
0.0894
Gnomad4 ASJ exome
AF:
0.0765
Gnomad4 EAS exome
AF:
0.0380
Gnomad4 SAS exome
AF:
0.0457
Gnomad4 FIN exome
AF:
0.00739
Gnomad4 NFE exome
AF:
0.0124
Gnomad4 OTH exome
AF:
0.0249
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0205
AC:
3105
AN:
151492
Hom.:
64
Cov.:
31
AF XY:
0.0217
AC XY:
1604
AN XY:
73990
show subpopulations
Gnomad4 AFR
AF:
0.00922
Gnomad4 AMR
AF:
0.0576
Gnomad4 ASJ
AF:
0.0689
Gnomad4 EAS
AF:
0.0498
Gnomad4 SAS
AF:
0.0438
Gnomad4 FIN
AF:
0.0102
Gnomad4 NFE
AF:
0.0138
Gnomad4 OTH
AF:
0.0381
Alfa
AF:
0.0154
Hom.:
11
Bravo
AF:
0.0264
Asia WGS
AF:
0.0320
AC:
110
AN:
3478
EpiCase
AF:
0.0195
EpiControl
AF:
0.0212

ClinVar

Significance: Benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsNov 14, 2017- -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 29, 2023- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015This variant is associated with the following publications: (PMID: 32022405) -
Holoprosencephaly 2 Benign:2
Benign, criteria provided, single submitterclinical testingInvitaeJan 30, 2024- -
Benign, no assertion criteria providedcurationGeneReviewsAug 29, 2013- -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.50
Cadd
Benign
14
Dann
Benign
0.96

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.

Other links and lift over

dbSNP: rs78018362; hg19: chr2-45169333; API