rs45549246
Positions:
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_007374.3(SIX6):āc.614T>Gā(p.Leu205Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00291 in 1,612,752 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.0032 ( 4 hom., cov: 33)
Exomes š: 0.0029 ( 17 hom. )
Consequence
SIX6
NM_007374.3 missense
NM_007374.3 missense
Scores
1
4
14
Clinical Significance
Conservation
PhyloP100: 4.75
Genes affected
SIX6 (HGNC:10892): (SIX homeobox 6) The protein encoded by this gene is a homeobox protein that is similar to the Drosophila 'sine oculis' gene product. This gene is found in a cluster of related genes on chromosome 14 and is thought to be involved in eye development. Defects in this gene are a cause of isolated microphthalmia with cataract type 2 (MCOPCT2). [provided by RefSeq, Jul 2008]
C14orf39 (HGNC:19849): (chromosome 14 open reading frame 39) Predicted to be involved in gamete generation and meiosis I. Predicted to be located in chromosome. Predicted to be active in central element. Implicated in primary ovarian insufficiency 18 and spermatogenic failure 52. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -13 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.0074677467).
BP6
?
Variant 14-60511125-T-G is Benign according to our data. Variant chr14-60511125-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 522355.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}. Variant chr14-60511125-T-G is described in Lovd as [Benign]. Variant chr14-60511125-T-G is described in Lovd as [Likely_benign].
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00321 (488/152192) while in subpopulation NFE AF= 0.00504 (343/67990). AF 95% confidence interval is 0.0046. There are 4 homozygotes in gnomad4. There are 235 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 488 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SIX6 | NM_007374.3 | c.614T>G | p.Leu205Arg | missense_variant | 2/2 | ENST00000327720.6 | |
C14orf39 | XM_047431324.1 | c.-144+4270A>C | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SIX6 | ENST00000327720.6 | c.614T>G | p.Leu205Arg | missense_variant | 2/2 | 1 | NM_007374.3 | P1 | |
C14orf39 | ENST00000556799.1 | c.-144+4270A>C | intron_variant | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.00322 AC: 489AN: 152074Hom.: 4 Cov.: 33
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GnomAD3 exomes AF: 0.00312 AC: 763AN: 244246Hom.: 4 AF XY: 0.00334 AC XY: 446AN XY: 133430
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GnomAD4 exome AF: 0.00288 AC: 4209AN: 1460560Hom.: 17 Cov.: 32 AF XY: 0.00297 AC XY: 2158AN XY: 726634
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GnomAD4 genome ? AF: 0.00321 AC: 488AN: 152192Hom.: 4 Cov.: 33 AF XY: 0.00316 AC XY: 235AN XY: 74406
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ExAC
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389
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 17, 2018 | This variant is associated with the following publications: (PMID: 28717659, 28499933, 24875647) - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2022 | SIX6: BS2 - |
Anophthalmia-microphthalmia syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
not specified Benign:1
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Colobomatous optic disc-macular atrophy-chorioretinopathy syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Oct 21, 2015 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Uncertain
D
MetaRNN
Benign
T
MetaSVM
Uncertain
T
MutationAssessor
Benign
L
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at