19-45765544-G-C
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_175875.5(SIX5):āc.2177C>Gā(p.Thr726Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,128 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: not found (cov: 33)
Exomes š: 0.0000014 ( 0 hom. )
Consequence
SIX5
NM_175875.5 missense
NM_175875.5 missense
Scores
2
12
5
Clinical Significance
Conservation
PhyloP100: 8.07
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 Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SIX5 | NM_175875.5 | c.2177C>G | p.Thr726Ser | 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.2177C>G | p.Thr726Ser | missense_variant | 3/3 | 1 | NM_175875.5 | ENSP00000316842 | P1 | |
ENST00000559756.1 | n.760G>C | non_coding_transcript_exon_variant | 1/2 | 3 | ||||||
SIX5 | ENST00000560160.1 | c.*387C>G | 3_prime_UTR_variant | 2/2 | 2 | ENSP00000453239 | ||||
SIX5 | ENST00000560168.1 | c.*1603C>G | 3_prime_UTR_variant | 3/3 | 4 | ENSP00000453189 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251208Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135882
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461128Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 726898
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GnomAD4 genome Cov.: 33
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33
Bravo
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 10, 2022 | The c.2177C>G (p.T726S) alteration is located in exon 3 (coding exon 3) of the SIX5 gene. This alteration results from a C to G substitution at nucleotide position 2177, causing the threonine (T) at amino acid position 726 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
.;T;T
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
N;N;.
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
.;N;.
REVEL
Uncertain
Sift
Uncertain
.;D;.
Sift4G
Uncertain
.;T;D
Polyphen
D;D;.
Vest4
0.58, 0.69
MutPred
Gain of phosphorylation at T726 (P = 0.0806);Gain of phosphorylation at T726 (P = 0.0806);.;
MVP
0.98
MPC
0.29
ClinPred
D
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