rs776132522

Variant names:

• chr12-131895053-C-A
• rs776132522
• NM_003565.4:c.52C>A

Your query was ambiguous. Multiple possible variants found:

• chr12-131895053-C-A
• chr12-131895053-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003565.4(ULK1):​c.52C>A​(p.Arg18Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,434,264 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R18C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ULK1 NM_003565.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.749
• Publications: 1 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18664414).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003565.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ULK1	NM_003565.4	MANE Select	c.52C>A	p.Arg18Ser	missense	Exon 1 of 28	NP_003556.2	O75385

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ULK1	ENST00000321867.6	TSL:1 MANE Select	c.52C>A	p.Arg18Ser	missense	Exon 1 of 28	ENSP00000324560.3	O75385
	ULK1	ENST00000939866.1		c.52C>A	p.Arg18Ser	missense	Exon 1 of 28	ENSP00000609925.1
	ULK1	ENST00000939867.1		c.52C>A	p.Arg18Ser	missense	Exon 1 of 28	ENSP00000609926.1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1434264 Hom.: 0 Cov.: 32 AF XY: 0.00000140 AC XY: 1 AN XY: 712980

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32476

American (AMR) AF: 0.0000236 AC: 1 AN: 42412

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25564

East Asian (EAS) AF: 0.0000265 AC: 1 AN: 37800

South Asian (SAS) AF: 0.00 AC: 0 AN: 83506

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42264

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105082

Other (OTH) AF: 0.00 AC: 0 AN: 59454

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 26

Alfa AF: 0.0000718 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	24
DANN	Benign	0.85
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.15	N
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.91	L
PhyloP100		0.75
PrimateAI	Pathogenic	0.96	D
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.077
Sift	Benign	0.27	T
Sift4G	Benign	0.22	T
Polyphen		0.079	B
Vest4		0.28
MutPred		0.60		Gain of disorder (P = 0.0654)
MVP		0.23
MPC		1.4
ClinPred		0.56	D
GERP RS		0.82
PromoterAI		0.054	Neutral
Varity_R		0.59
gMVP		0.90
Mutation Taster		=41/59	disease causing

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

Other links and lift over

dbSNP: rs776132522; hg19: chr12-132379598; COSMIC: COSV100416616; COSMIC: COSV100416616;