Variant 12-131913767-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_003565.4(ULK1):c.1178C>T(p.Ala393Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000925 in 1,567,260 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000071 ( 1 hom. )

Consequence

ULK1
NM_003565.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.83

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]

ULK1 links:

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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=0.04283014).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ULK1	NM_003565.4 linkuse as main transcript	c.1178C>T	p.Ala393Val	missense_variant	15/28	ENST00000321867.6	NP_003556.2
ULK1	XM_011538798.4 linkuse as main transcript	c.1178C>T	p.Ala393Val	missense_variant	15/28		XP_011537100.1
ULK1	XM_011538799.3 linkuse as main transcript	c.1178C>T	p.Ala393Val	missense_variant	15/28		XP_011537101.1
ULK1	XR_007063134.1 linkuse as main transcript	n.1558C>T		non_coding_transcript_exon_variant	15/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ULK1	ENST00000321867.6 linkuse as main transcript	c.1178C>T	p.Ala393Val	missense_variant	15/28	1	NM_003565.4	ENSP00000324560	P1

Frequencies

GnomAD3 genomes

AF:

0.000283

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000604

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000786

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000121

AC:

AN:

214632

Hom.:

AF XY:

0.000127

AC XY:

AN XY:

118084

show subpopulations

Gnomad AFR exome

AF:

0.000297

Gnomad AMR exome

AF:

0.000144

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000607

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000203

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000714

AC:

101

AN:

1415052

Hom.:

Cov.:

AF XY:

0.0000925

AC XY:

AN XY:

702482

show subpopulations

Gnomad4 AFR exome

AF:

0.000458

Gnomad4 AMR exome

AF:

0.000235

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000627

Gnomad4 FIN exome

AF:

0.0000194

Gnomad4 NFE exome

AF:

0.0000184

Gnomad4 OTH exome

AF:

0.000103

GnomAD4 genome

AF:

0.000289

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.000626

Gnomad4 AMR

AF:

0.000785

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000101

Hom.:

Bravo

AF:

0.000423

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000124

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

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 submitter

clinical testing

Ambry Genetics

Nov 01, 2022

The c.1178C>T (p.A393V) alteration is located in exon 15 (coding exon 15) of the ULK1 gene. This alteration results from a C to T substitution at nucleotide position 1178, causing the alanine (A) at amino acid position 393 to be replaced by a valine (V). 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

0.11

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.27

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.76

M_CAP

Benign

0.021

MetaRNN

Benign

0.043

MetaSVM

Benign

-0.78

MutationAssessor

Benign

1.4

MutationTaster

Benign

0.95

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.99

REVEL

Benign

0.092

Sift

Benign

0.092

Sift4G

Benign

0.37

Polyphen

0.024

Vest4

0.26

MVP

0.20

MPC

0.086

ClinPred

0.016

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.035

gMVP

0.44

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over