rs370941478

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS1

The NM_005413.4(SIX3):​c.831G>A​(p.Pro277Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000405 in 1,578,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P277P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00043 ( 0 hom. )

Consequence

SIX3
NM_005413.4 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.18

Publications

1 publications found
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-AS1 (HGNC:40532): (SIX3 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.45).
BP6
Variant 2-44944592-G-A is Benign according to our data. Variant chr2-44944592-G-A is described in CliVar as Likely_benign. Clinvar id is 259763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-44944592-G-A is described in CliVar as Likely_benign. Clinvar id is 259763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=1.18 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000204 (31/152218) while in subpopulation NFE AF = 0.000397 (27/68028). AF 95% confidence interval is 0.00028. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SIX3NM_005413.4 linkc.831G>A p.Pro277Pro synonymous_variant Exon 2 of 2 ENST00000260653.5 NP_005404.1 O95343

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SIX3ENST00000260653.5 linkc.831G>A p.Pro277Pro synonymous_variant Exon 2 of 2 1 NM_005413.4 ENSP00000260653.3 O95343
SIX3-AS1ENST00000760561.1 linkn.160C>T non_coding_transcript_exon_variant Exon 1 of 2
ENSG00000225156ENST00000760330.1 linkn.135+10216G>A intron_variant Intron 1 of 1
SIX3-AS1ENST00000760560.1 linkn.388+806C>T intron_variant Intron 1 of 1

Frequencies

GnomAD3 genomes
AF:
0.000204
AC:
31
AN:
152218
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000397
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000212
AC:
41
AN:
193448
AF XY:
0.000176
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000623
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000432
Gnomad OTH exome
AF:
0.000390
GnomAD4 exome
AF:
0.000427
AC:
609
AN:
1426144
Hom.:
0
Cov.:
31
AF XY:
0.000421
AC XY:
298
AN XY:
708180
show subpopulations
African (AFR)
AF:
0.0000916
AC:
3
AN:
32756
American (AMR)
AF:
0.000139
AC:
6
AN:
43094
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25744
East Asian (EAS)
AF:
0.00
AC:
0
AN:
38136
South Asian (SAS)
AF:
0.00
AC:
0
AN:
83824
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
36528
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5616
European-Non Finnish (NFE)
AF:
0.000526
AC:
579
AN:
1101178
Other (OTH)
AF:
0.000354
AC:
21
AN:
59268
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.486
Heterozygous variant carriers
0
38
76
115
153
191
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
26
52
78
104
130
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000204
AC:
31
AN:
152218
Hom.:
0
Cov.:
33
AF XY:
0.000108
AC XY:
8
AN XY:
74370
show subpopulations
African (AFR)
AF:
0.0000482
AC:
2
AN:
41470
American (AMR)
AF:
0.000131
AC:
2
AN:
15288
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3466
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5190
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10622
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.000397
AC:
27
AN:
68028
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.501
Heterozygous variant carriers
0
2
4
5
7
9
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000108
Hom.:
0
Bravo
AF:
0.000204

ClinVar

Significance: Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
-
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Holoprosencephaly 2 Benign:1
Nov 02, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Benign:1
May 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

SIX3: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.45
CADD
Benign
6.9
DANN
Benign
0.97
PhyloP100
1.2
Mutation Taster
=99/1
polymorphism

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

Other links and lift over

dbSNP: rs370941478; hg19: chr2-45171731; API