chr12-131914363-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003565.4(ULK1):​c.1259C>T​(p.Pro420Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000931 in 1,610,964 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 34)
Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

ULK1
NM_003565.4 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.635
Variant links:
Genes affected
ULK1 (HGNC:12558): (unc-51 like autophagy activating kinase 1) Enables identical protein binding activity; protein serine/threonine kinase activity; and small GTPase binding activity. Involved in several processes, including autophagosome assembly; positive regulation by symbiont of host autophagy; and protein phosphorylation. Located in autophagosome; cytosol; and phagophore assembly site membrane. Is extrinsic component of autophagosome membrane; extrinsic component of omegasome membrane; and extrinsic component of phagophore assembly site membrane. Part of Atg1/ULK1 kinase complex. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06653234).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ULK1NM_003565.4 linkuse as main transcriptc.1259C>T p.Pro420Leu missense_variant 16/28 ENST00000321867.6
ULK1XM_011538798.4 linkuse as main transcriptc.1259C>T p.Pro420Leu missense_variant 16/28
ULK1XM_011538799.3 linkuse as main transcriptc.1259C>T p.Pro420Leu missense_variant 16/28
ULK1XR_007063134.1 linkuse as main transcriptn.1639C>T non_coding_transcript_exon_variant 16/23

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ULK1ENST00000321867.6 linkuse as main transcriptc.1259C>T p.Pro420Leu missense_variant 16/281 NM_003565.4 P1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152256
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000121
AC:
3
AN:
247970
Hom.:
0
AF XY:
0.0000223
AC XY:
3
AN XY:
134708
show subpopulations
Gnomad AFR exome
AF:
0.0000621
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000891
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000823
AC:
12
AN:
1458708
Hom.:
0
Cov.:
30
AF XY:
0.0000110
AC XY:
8
AN XY:
725754
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
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:
0.00000630
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152256
Hom.:
0
Cov.:
34
AF XY:
0.0000134
AC XY:
1
AN XY:
74388
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000441
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

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 GeneticsJan 11, 2023The c.1259C>T (p.P420L) alteration is located in exon 16 (coding exon 16) of the ULK1 gene. This alteration results from a C to T substitution at nucleotide position 1259, causing the proline (P) at amino acid position 420 to be replaced by a leucine (L). 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
0.083
BayesDel_addAF
Benign
-0.24
T
BayesDel_noAF
Benign
-0.40
CADD
Benign
19
DANN
Uncertain
0.98
DEOGEN2
Benign
0.23
T
Eigen
Benign
-0.43
Eigen_PC
Benign
-0.39
FATHMM_MKL
Benign
0.39
N
LIST_S2
Uncertain
0.87
D
M_CAP
Benign
0.021
T
MetaRNN
Benign
0.067
T
MetaSVM
Benign
-0.64
T
MutationAssessor
Benign
1.4
L
MutationTaster
Benign
0.99
D;N
PrimateAI
Benign
0.30
T
PROVEAN
Uncertain
-2.6
D
REVEL
Benign
0.11
Sift
Benign
0.036
D
Sift4G
Uncertain
0.018
D
Polyphen
0.079
B
Vest4
0.12
MutPred
0.27
Loss of relative solvent accessibility (P = 0.0186);
MVP
0.15
MPC
0.087
ClinPred
0.30
T
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.10
gMVP
0.15

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.16
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: rs917929816; hg19: chr12-132398908; API