chr15-74837753-T-C

Variant summary

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

The NM_001099436.4(ULK3):ā€‹c.1333A>Gā€‹(p.Lys445Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 1,596,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K445R) has been classified as Likely benign.

Frequency

Genomes: š‘“ 0.000066 ( 0 hom., cov: 31)
Exomes š‘“: 0.00015 ( 0 hom. )

Consequence

ULK3
NM_001099436.4 missense, splice_region

Scores

5
14
Splicing: ADA: 0.3388
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.27
Variant links:
Genes affected
ULK3 (HGNC:19703): (unc-51 like kinase 3) Enables protein serine/threonine kinase activity. Involved in several processes, including fibroblast activation; protein autophosphorylation; and regulation of smoothened signaling pathway. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

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=0.23675382).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ULK3NM_001099436.4 linkuse as main transcriptc.1333A>G p.Lys445Glu missense_variant, splice_region_variant 14/16 ENST00000440863.7 NP_001092906.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ULK3ENST00000440863.7 linkuse as main transcriptc.1333A>G p.Lys445Glu missense_variant, splice_region_variant 14/162 NM_001099436.4 ENSP00000400312 A1Q6PHR2-1

Frequencies

GnomAD3 genomes
AF:
0.0000659
AC:
10
AN:
151660
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000243
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.000133
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000495
AC:
11
AN:
222372
Hom.:
0
AF XY:
0.0000332
AC XY:
4
AN XY:
120390
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000111
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000150
AC:
217
AN:
1444978
Hom.:
0
Cov.:
40
AF XY:
0.000153
AC XY:
110
AN XY:
717204
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000387
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000182
Gnomad4 OTH exome
AF:
0.000251
GnomAD4 genome
AF:
0.0000659
AC:
10
AN:
151660
Hom.:
0
Cov.:
31
AF XY:
0.0000675
AC XY:
5
AN XY:
74046
show subpopulations
Gnomad4 AFR
AF:
0.0000243
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000133
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000115
Hom.:
0
Bravo
AF:
0.0000756
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.0000414
AC:
5

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 submitterclinical testingAmbry GeneticsDec 20, 2023The c.1333A>G (p.K445E) alteration is located in exon 14 (coding exon 14) of the ULK3 gene. This alteration results from a A to G substitution at nucleotide position 1333, causing the lysine (K) at amino acid position 445 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.28
BayesDel_addAF
Benign
-0.070
T
BayesDel_noAF
Benign
-0.14
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.051
T;.
Eigen
Uncertain
0.19
Eigen_PC
Uncertain
0.26
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Benign
0.86
D;D
M_CAP
Benign
0.030
D
MetaRNN
Benign
0.24
T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
2.0
M;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.60
T
PROVEAN
Benign
-0.23
N;N
REVEL
Benign
0.17
Sift
Benign
0.34
T;T
Sift4G
Benign
0.64
T;T
Polyphen
0.15
B;.
Vest4
0.41
MutPred
0.25
.;Loss of MoRF binding (P = 0.0016);
MVP
0.49
MPC
0.40
ClinPred
0.41
T
GERP RS
5.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.48
gMVP
0.26

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.34
dbscSNV1_RF
Benign
0.50
SpliceAI score (max)
0.010
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: rs773968655; hg19: chr15-75130094; API