19-45765818-G-T

Variant summary

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

The NM_175875.5(SIX5):​c.1903C>A​(p.Pro635Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,450,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P635S) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SIX5
NM_175875.5 missense

Scores

1
18

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.360
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=0.09326479).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SIX5NM_175875.5 linkc.1903C>A p.Pro635Thr missense_variant Exon 3 of 3 ENST00000317578.7 NP_787071.3 Q8N196

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SIX5ENST00000317578.7 linkc.1903C>A p.Pro635Thr missense_variant Exon 3 of 3 1 NM_175875.5 ENSP00000316842.4 Q8N196
SIX5ENST00000560160 linkc.*113C>A 3_prime_UTR_variant Exon 2 of 2 2 ENSP00000453239.2 H0YLK1
SIX5ENST00000560168 linkc.*1329C>A 3_prime_UTR_variant Exon 3 of 3 4 ENSP00000453189.2 H0YLF6
ENSG00000259605ENST00000559756.1 linkn.1034G>T non_coding_transcript_exon_variant Exon 1 of 2 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.90e-7
AC:
1
AN:
1450114
Hom.:
0
Cov.:
82
AF XY:
0.00
AC XY:
0
AN XY:
721798
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.079
BayesDel_addAF
Benign
-0.10
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
14
DANN
Benign
0.97
DEOGEN2
Benign
0.093
T;T;T
Eigen
Benign
-0.72
Eigen_PC
Benign
-0.65
FATHMM_MKL
Benign
0.14
N
LIST_S2
Benign
0.61
.;T;T
M_CAP
Benign
0.076
D
MetaRNN
Benign
0.093
T;T;T
MetaSVM
Benign
-0.57
T
MutationAssessor
Benign
0.69
N;N;.
PrimateAI
Uncertain
0.51
T
PROVEAN
Benign
-0.090
.;N;.
REVEL
Benign
0.23
Sift
Benign
0.27
.;T;.
Sift4G
Benign
0.58
.;T;D
Polyphen
0.0040
B;B;.
Vest4
0.084, 0.076
MutPred
0.27
Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);.;
MVP
0.83
MPC
0.048
ClinPred
0.051
T
GERP RS
-0.76
Varity_R
0.048
gMVP
0.20

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: chr19-46269076; API