NM_001099436.4:c.1385C>T

Variant names:

• chr15-74837386-G-A
• rs769848635
• NM_001099436.4:c.1385C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001099436.4(ULK3):​c.1385C>T​(p.Ser462Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,612,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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: 31)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: ULK3 NM_001099436.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.16
• Publications: 0 publications found

Genes affected

ULK3 (HGNC:19703): (unc-51 like kinase 3) Enables protein serine/threonine kinase activity. Involved in several processes, including fibroblast activation; protein autophosphorylation; and regulation of smoothened signaling pathway. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06348014).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001099436.4. 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
	ULK3	NM_001099436.4	MANE Select	c.1385C>T	p.Ser462Leu	missense	Exon 15 of 16	NP_001092906.3	Q6PHR2-1
	ULK3	NM_001411082.1		c.1418C>T	p.Ser473Leu	missense	Exon 15 of 16	NP_001398011.1	Q6PHR2-4
	ULK3	NM_001284364.3		c.1379C>T	p.Ser460Leu	missense	Exon 15 of 16	NP_001271293.2	Q6PHR2-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ULK3	ENST00000440863.7	TSL:2 MANE Select	c.1385C>T	p.Ser462Leu	missense	Exon 15 of 16	ENSP00000400312.2	Q6PHR2-1
	ULK3	ENST00000569437.5	TSL:1	c.1379C>T	p.Ser460Leu	missense	Exon 15 of 16	ENSP00000456051.1	Q6PHR2-3
	ULK3	ENST00000566479.5	TSL:1	n.1571C>T		non_coding_transcript_exon	Exon 14 of 15

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152128 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000811 AC: 2 AN: 246582 AF XY: 0.00000747

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000301 AC: 44 AN: 1460802 Hom.: 0 Cov.: 35 AF XY: 0.0000303 AC XY: 22 AN XY: 726626

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44536

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86036

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000351 AC: 39 AN: 1111522

Other (OTH) AF: 0.0000331 AC: 2 AN: 60352

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152128 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74300

African (AFR) AF: 0.0000241 AC: 1 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.098	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.2
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.068
Sift	Benign	0.074	T
Sift4G	Uncertain	0.023	D
Polyphen		0.0030	B
Vest4		0.23
MutPred		0.15		Loss of phosphorylation at S473 (P = 0.0194)
MVP		0.44
MPC		0.24
ClinPred		0.11	T
GERP RS		1.1
Varity_R		0.096
gMVP		0.13
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs769848635; hg19: chr15-75129727;