15-74837435-T-C

Position:

• chr15-74837435-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001099436.4(ULK3):​c.1336A>G​(p.Met446Val) 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. 15/23 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ULK3 NM_001099436.4 missense, splice_region
• Scores: Splicing: ADA: 0.00009332
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.90

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13368604).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ULK3	NM_001099436.4	c.1336A>G	p.Met446Val	missense_variant, splice_region_variant	15/16	ENST00000440863.7	NP_001092906.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ULK3	ENST00000440863.7	c.1336A>G	p.Met446Val	missense_variant, splice_region_variant	15/16	2	NM_001099436.4	ENSP00000400312	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2022

The c.1336A>G (p.M446V) alteration is located in exon 15 (coding exon 15) of the ULK3 gene. This alteration results from a A to G substitution at nucleotide position 1336, causing the methionine (M) at amino acid position 446 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	0.14
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.053	T;.;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.68	T;T;T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.095	T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.9	L;.;.
MutationTaster	Benign	0.84	N;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.40	N;N;N
REVEL	Benign	0.12
Sift	Benign	0.31	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.66	P;D;.
Vest4		0.27
MutPred		0.24		.;.;Gain of methylation at K456 (P = 0.0182);
MVP		0.79
MPC		0.28
ClinPred		0.099	T
GERP RS		3.9
Varity_R		0.18
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000093
dbscSNV1_RF	Benign	0.024
SpliceAI score (max)		0.18		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-75129776;