rs3774372

Variant names:

• chr3-41835922-T-C
• rs3774372
• NM_017886.4:c.1706A>G

Variant summary

Our verdict is Benign. The variant received -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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• 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
• Publications: 96 publications found

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]

ULK4 Gene-Disease associations (from GenCC):

• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
ULK4	NM_017886.4	c.1706A>G	p.Lys569Arg	missense_variant	Exon 18 of 37	ENST00000301831.9	NP_060356.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ULK4	ENST00000301831.9	c.1706A>G	p.Lys569Arg	missense_variant	Exon 18 of 37	2	NM_017886.4	ENSP00000301831.4
ULK4	ENST00000460406.1	n.187A>G		non_coding_transcript_exon_variant	Exon 3 of 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

GnomAD2 exomes AF: 0.168 AC: 41808 AN: 248288 AF XY: 0.171

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 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

African (AFR) AF: 0.207 AC: 6889 AN: 33270

American (AMR) AF: 0.114 AC: 5073 AN: 44536

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 4375 AN: 26052

East Asian (EAS) AF: 0.146 AC: 5790 AN: 39588

South Asian (SAS) AF: 0.178 AC: 15246 AN: 85598

European-Finnish (FIN) AF: 0.212 AC: 11316 AN: 53316

Middle Eastern (MID) AF: 0.284 AC: 1633 AN: 5742

European-Non Finnish (NFE) AF: 0.161 AC: 177822 AN: 1107858

Other (OTH) AF: 0.173 AC: 10434 AN: 60144

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

African (AFR) AF: 0.205 AC: 8454 AN: 41246

American (AMR) AF: 0.155 AC: 2364 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 590 AN: 3466

East Asian (EAS) AF: 0.164 AC: 847 AN: 5156

South Asian (SAS) AF: 0.185 AC: 888 AN: 4804

European-Finnish (FIN) AF: 0.221 AC: 2320 AN: 10492

Middle Eastern (MID) AF: 0.315 AC: 92 AN: 292

European-Non Finnish (NFE) AF: 0.167 AC: 11358 AN: 67906

Other (OTH) AF: 0.197 AC: 415 AN: 2110

Alfa AF: 0.175 Hom.: 7584

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

Oct 21, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		4.3
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
Mutation Taster		=85/15	polymorphism (auto)

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