19-45765518-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_175875.5(SIX5):​c.2203G>C​(p.Glu735Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

SIX5
NM_175875.5 missense

Scores

8
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.46
Variant links:
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.20195433).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SIX5NM_175875.5 linkuse as main transcriptc.2203G>C p.Glu735Gln missense_variant 3/3 ENST00000317578.7 NP_787071.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SIX5ENST00000317578.7 linkuse as main transcriptc.2203G>C p.Glu735Gln missense_variant 3/31 NM_175875.5 ENSP00000316842 P1
ENST00000559756.1 linkuse as main transcriptn.734C>G non_coding_transcript_exon_variant 1/23
SIX5ENST00000560160.1 linkuse as main transcriptc.*413G>C 3_prime_UTR_variant 2/22 ENSP00000453239
SIX5ENST00000560168.1 linkuse as main transcriptc.*1629G>C 3_prime_UTR_variant 3/34 ENSP00000453189

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 06, 2023This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 735 of the SIX5 protein (p.Glu735Gln). This variant is not present in population databases (gnomAD no frequency). 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: 1933833). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.33
BayesDel_addAF
Benign
0.0088
T
BayesDel_noAF
Benign
-0.23
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.14
T;T;T
Eigen
Benign
0.14
Eigen_PC
Uncertain
0.25
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.77
.;T;T
M_CAP
Uncertain
0.14
D
MetaRNN
Benign
0.20
T;T;T
MetaSVM
Uncertain
0.28
D
MutationAssessor
Benign
0.34
N;N;.
MutationTaster
Benign
0.90
D;D
PrimateAI
Uncertain
0.61
T
PROVEAN
Benign
-0.65
.;N;.
REVEL
Uncertain
0.34
Sift
Uncertain
0.0030
.;D;.
Sift4G
Benign
0.26
.;T;T
Polyphen
0.76
P;P;.
Vest4
0.24, 0.16
MutPred
0.056
Gain of relative solvent accessibility (P = 0.1894);Gain of relative solvent accessibility (P = 0.1894);.;
MVP
0.88
MPC
0.11
ClinPred
0.38
T
GERP RS
4.5
Varity_R
0.17
gMVP
0.22

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-46268776; API