19-45765532-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS2

The NM_175875.5(SIX5):​c.2189C>T​(p.Ser730Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000738 in 1,613,280 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.00011 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000070 ( 1 hom. )

Consequence

SIX5
NM_175875.5 missense

Scores

5
9
5

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 6.40
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.37406826).
BP6
Variant 19-45765532-G-A is Benign according to our data. Variant chr19-45765532-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1315723.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
BS2
High AC in GnomAd4 at 17 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SIX5NM_175875.5 linkuse as main transcriptc.2189C>T p.Ser730Leu 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.2189C>T p.Ser730Leu missense_variant 3/31 NM_175875.5 ENSP00000316842 P1
ENST00000559756.1 linkuse as main transcriptn.748G>A non_coding_transcript_exon_variant 1/23
SIX5ENST00000560160.1 linkuse as main transcriptc.*399C>T 3_prime_UTR_variant 2/22 ENSP00000453239
SIX5ENST00000560168.1 linkuse as main transcriptc.*1615C>T 3_prime_UTR_variant 3/34 ENSP00000453189

Frequencies

GnomAD3 genomes
AF:
0.000112
AC:
17
AN:
152188
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
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:
0.000206
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000677
AC:
17
AN:
251216
Hom.:
0
AF XY:
0.0000957
AC XY:
13
AN XY:
135874
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000123
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000698
AC:
102
AN:
1461092
Hom.:
1
Cov.:
29
AF XY:
0.0000784
AC XY:
57
AN XY:
726872
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000894
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000809
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.000112
AC:
17
AN:
152188
Hom.:
0
Cov.:
33
AF XY:
0.0000538
AC XY:
4
AN XY:
74342
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000206
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000965
Hom.:
0
Bravo
AF:
0.0000945
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000659
AC:
8
EpiCase
AF:
0.000109
EpiControl
AF:
0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 23, 2021This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 730 of the SIX5 protein (p.Ser730Leu). This variant is present in population databases (rs150045306, gnomAD 0.01%). This missense change has been observed in individual(s) with bilateral kidney agenesis (PMID: 28566479). 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. -
Likely benign, criteria provided, single submitterclinical testingGeneDxJan 29, 2021This variant is associated with the following publications: (PMID: 28566479) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.62
BayesDel_addAF
Uncertain
0.014
T
BayesDel_noAF
Uncertain
0.020
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.19
T;T;T
Eigen
Uncertain
0.52
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.86
.;D;D
M_CAP
Pathogenic
0.47
D
MetaRNN
Benign
0.37
T;T;T
MetaSVM
Uncertain
0.28
D
MutationAssessor
Benign
0.69
N;N;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.85
D
PROVEAN
Benign
-1.3
.;N;.
REVEL
Uncertain
0.49
Sift
Pathogenic
0.0
.;D;.
Sift4G
Uncertain
0.0040
.;D;D
Polyphen
1.0
D;D;.
Vest4
0.61, 0.43
MVP
0.95
MPC
0.29
ClinPred
0.33
T
GERP RS
4.5
Varity_R
0.26
gMVP
0.46

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs150045306; hg19: chr19-46268790; API