chr12-131910799-C-A

Variant names:

• chr12-131910799-C-A
• rs767820098
• NM_003565.4:c.947C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003565.4(ULK1):​c.947C>A​(p.Pro316Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. P316L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ULK1 NM_003565.4 missense, splice_region
• Scores: Splicing: ADA: 0.4157
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.09
• Publications: 0 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30098313).

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.947C>A	p.Pro316Gln	missense splice_region	Exon 12 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.947C>A	p.Pro316Gln	missense splice_region	Exon 12 of 28	ENSP00000324560.3	O75385
	ULK1	ENST00000939866.1		c.947C>A	p.Pro316Gln	missense splice_region	Exon 12 of 28	ENSP00000609925.1
	ULK1	ENST00000939867.1		c.944C>A	p.Pro315Gln	missense splice_region	Exon 12 of 28	ENSP00000609926.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.1
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.14
Sift	Benign	0.043	D
Sift4G	Benign	0.16	T
Polyphen		0.99	D
Vest4		0.47
MutPred		0.30		Gain of solvent accessibility (P = 6e-04)
MVP		0.15
MPC		0.45
ClinPred		0.98	D
GERP RS		4.2
Varity_R		0.44
gMVP		0.19
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.42
dbscSNV1_RF	Benign	0.54
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

Other links and lift over

dbSNP: rs767820098; hg19: chr12-132395344;