chr12-131909833-C-T

Position:

chr12-131909833-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_003565.4(ULK1):c.725C>T(p.Thr242Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00299 in 1,611,584 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/23 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 Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0022 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0031 ( 13 hom. )

Consequence

ULK1
NM_003565.4 missense, splice_region

Scores

Splicing: ADA: 0.0001482

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.290

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008176357).

BP6

Variant 12-131909833-C-T is Benign according to our data. Variant chr12-131909833-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3044869.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ULK1	NM_003565.4 linkuse as main transcript	c.725C>T	p.Thr242Ile	missense_variant, splice_region_variant	9/28	ENST00000321867.6	NP_003556.2
ULK1	XM_011538798.4 linkuse as main transcript	c.725C>T	p.Thr242Ile	missense_variant, splice_region_variant	9/28		XP_011537100.1
ULK1	XM_011538799.3 linkuse as main transcript	c.725C>T	p.Thr242Ile	missense_variant, splice_region_variant	9/28		XP_011537101.1
ULK1	XR_007063134.1 linkuse as main transcript	n.1105C>T		splice_region_variant, non_coding_transcript_exon_variant	9/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ULK1	ENST00000321867.6 linkuse as main transcript	c.725C>T	p.Thr242Ile	missense_variant, splice_region_variant	9/28	1	NM_003565.4	ENSP00000324560	P1
ULK1	ENST00000537421.5 linkuse as main transcript	n.881C>T		splice_region_variant, non_coding_transcript_exon_variant	6/7	3

Frequencies

GnomAD3 genomes

AF:

0.00218

AC:

331

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.00367

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000376

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00341

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00203

AC:

496

AN:

244340

Hom.:

AF XY:

0.00189

AC XY:

252

AN XY:

133238

show subpopulations

Gnomad AFR exome

AF:

0.000512

Gnomad AMR exome

AF:

0.00388

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000395

Gnomad FIN exome

AF:

0.000334

Gnomad NFE exome

AF:

0.00286

Gnomad OTH exome

AF:

0.00403

GnomAD4 exome

AF:

0.00308

AC:

4488

AN:

1459358

Hom.:

Cov.:

AF XY:

0.00294

AC XY:

2137

AN XY:

725918

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.00412

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000372

Gnomad4 FIN exome

AF:

0.000520

Gnomad4 NFE exome

AF:

0.00367

Gnomad4 OTH exome

AF:

0.00242

GnomAD4 genome

AF:

0.00217

AC:

330

AN:

152226

Hom.:

Cov.:

AF XY:

0.00207

AC XY:

154

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.000457

Gnomad4 AMR

AF:

0.00360

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000376

Gnomad4 NFE

AF:

0.00341

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00224

Hom.:

Bravo

AF:

0.00244

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00291

AC:

ExAC

AF:

0.00164

AC:

199

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00300

EpiControl

AF:

0.00255

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

ULK1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 01, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.80

DEOGEN2

Benign

0.33

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.47

M_CAP

Benign

0.025

MetaRNN

Benign

0.0082

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.66

MutationTaster

Benign

1.0

PrimateAI

Benign

0.36

PROVEAN

Benign

-2.0

REVEL

Benign

0.10

Sift

Benign

0.17

Sift4G

Benign

0.14

Polyphen

0.0030

Vest4

0.21

MVP

0.40

MPC

1.1

ClinPred

0.0015

GERP RS

-4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.18

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00015

dbscSNV1_RF

Benign

0.024

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.

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