chr19-45765560-C-T
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Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS2
The NM_175875.5(SIX5):c.2161G>A(p.Glu721Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,613,336 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
SIX5
NM_175875.5 missense
NM_175875.5 missense
Scores
2
10
7
Clinical Significance
Conservation
PhyloP100: 3.10
Genes affected
SIX5 (HGNC:10891): (SIX homeobox 5) The protein encoded by this gene is a homeodomain-containing transcription factor that appears to function in the regulation of organogenesis. This gene is located downstream of the dystrophia myotonica-protein kinase gene. Mutations in this gene are a cause of branchiootorenal syndrome type 2. [provided by RefSeq, Jul 2009]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.2936442).
BP6
Variant 19-45765560-C-T is Benign according to our data. Variant chr19-45765560-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1524148.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
BS2
High AC in GnomAdExome4 at 23 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SIX5 | NM_175875.5 | c.2161G>A | p.Glu721Lys | missense_variant | 3/3 | ENST00000317578.7 | NP_787071.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SIX5 | ENST00000317578.7 | c.2161G>A | p.Glu721Lys | missense_variant | 3/3 | 1 | NM_175875.5 | ENSP00000316842 | P1 | |
ENST00000559756.1 | n.776C>T | non_coding_transcript_exon_variant | 1/2 | 3 | ||||||
SIX5 | ENST00000560160.1 | c.*371G>A | 3_prime_UTR_variant | 2/2 | 2 | ENSP00000453239 | ||||
SIX5 | ENST00000560168.1 | c.*1587G>A | 3_prime_UTR_variant | 3/3 | 4 | ENSP00000453189 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152226Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251132Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135852
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GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461110Hom.: 0 Cov.: 29 AF XY: 0.0000193 AC XY: 14AN XY: 726896
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152226Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74360
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 05, 2022 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 721 of the SIX5 protein (p.Glu721Lys). This variant is present in population databases (rs750672211, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with SIX5-related conditions. ClinVar contains an entry for this variant (Variation ID: 1524148). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 28, 2024 | 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Benign
N;N;.
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
.;N;.
REVEL
Uncertain
Sift
Uncertain
.;D;.
Sift4G
Benign
.;T;D
Polyphen
P;P;.
Vest4
0.64, 0.31
MutPred
Gain of ubiquitination at E721 (P = 0.009);Gain of ubiquitination at E721 (P = 0.009);.;
MVP
0.96
MPC
0.31
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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