rs3774372

Positions:

• chr3-41835922-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_017886.4(ULK4):​c.1706A>G​(p.Lys569Arg) variant causes a missense change. The variant allele was found at a frequency of 0.166 in 1,607,736 control chromosomes in the GnomAD database, including 22,874 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.18 (2563 hom., cov: 31)
  • Exomes 𝑓: 0.16 (20311 hom.)
• Consequence: ULK4 NM_017886.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 4.28

Genes affected

ULK4 (HGNC:15784): (unc-51 like kinase 4) This gene encodes a member of the unc-51-like serine/threonine kinase (STK) family. Members of this protein family play a role in neuronal growth and endocytosis. The encoded protein is likely involved in neurite branching, neurite elongation and neuronal migration. Genome-wide association studies (GWAS) indicate an association of variations in this gene with blood pressure and hypertension. Sequence variations in this gene may also be be associated with psychiatric disorders, including schizophrenia and bipolar disorder. Pseudogenes associated with this gene have been identified and are located on chromosome 15. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001639843).
• BP6: Variant 3-41835922-T-C is Benign according to our data. Variant chr3-41835922-T-C is described in ClinVar as [Benign]. Clinvar id is 3058867.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ULK4	NM_017886.4	c.1706A>G	p.Lys569Arg	missense_variant	18/37	ENST00000301831.9	NP_060356.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ULK4	ENST00000301831.9	c.1706A>G	p.Lys569Arg	missense_variant	18/37	2	NM_017886.4	ENSP00000301831	P1
ULK4	ENST00000460406.1	n.187A>G		non_coding_transcript_exon_variant	3/5	2

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27516 AN: 151516 Hom.: 2559 Cov.: 31

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.170

Gnomad EAS AF: 0.164

Gnomad SAS AF: 0.186

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.318

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.198

GnomAD3 exomes AF: 0.168 AC: 41808 AN: 248288 Hom.: 3860 AF XY: 0.171 AC XY: 23076 AN XY: 134728

Gnomad AFR exome AF: 0.203

Gnomad AMR exome AF: 0.111

Gnomad ASJ exome AF: 0.164

Gnomad EAS exome AF: 0.180

Gnomad SAS exome AF: 0.176

Gnomad FIN exome AF: 0.221

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.174

GnomAD4 exome AF: 0.164 AC: 238578 AN: 1456104 Hom.: 20311 Cov.: 31 AF XY: 0.164 AC XY: 119076 AN XY: 724492

Gnomad4 AFR exome AF: 0.207

Gnomad4 AMR exome AF: 0.114

Gnomad4 ASJ exome AF: 0.168

Gnomad4 EAS exome AF: 0.146

Gnomad4 SAS exome AF: 0.178

Gnomad4 FIN exome AF: 0.212

Gnomad4 NFE exome AF: 0.161

Gnomad4 OTH exome AF: 0.173

GnomAD4 genome AF: 0.182 AC: 27525 AN: 151632 Hom.: 2563 Cov.: 31 AF XY: 0.184 AC XY: 13623 AN XY: 74080

Gnomad4 AFR AF: 0.205

Gnomad4 AMR AF: 0.155

Gnomad4 ASJ AF: 0.170

Gnomad4 EAS AF: 0.164

Gnomad4 SAS AF: 0.185

Gnomad4 FIN AF: 0.221

Gnomad4 NFE AF: 0.167

Gnomad4 OTH AF: 0.197

Alfa AF: 0.174 Hom.: 5173

Bravo AF: 0.178

TwinsUK AF: 0.167 AC: 619

ALSPAC AF: 0.157 AC: 606

ESP6500AA AF: 0.209 AC: 766

ESP6500EA AF: 0.168 AC: 1373

ExAC AF: 0.171 AC: 20699

Asia WGS AF: 0.160 AC: 555 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

ULK4-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

This variant is classified as 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	0.087
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0018	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	0.11	P
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.092
Sift	Benign	0.32	T
Sift4G	Benign	0.31	T
Polyphen		0.78	P
Vest4		0.12
MPC		0.045
ClinPred		0.010	T
GERP RS		5.5
Varity_R		0.17
gMVP		0.36

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

Publications

LitVar

Other links and lift over

dbSNP: rs3774372; hg19: chr3-41877414; COSMIC: COSV57199232;