3-41883906-C-T

Variant names:

• chr3-41883906-C-T
• rs1052501
• NM_017886.4:c.1624G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017886.4(ULK4):​c.1624G>A​(p.Ala542Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.807 in 1,606,958 control chromosomes in the GnomAD database, including 533,317 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A542A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.69 (39499 hom., cov: 33)
  • Exomes 𝑓: 0.82 (493818 hom.)
• Consequence: ULK4 NM_017886.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0120
• Publications: 87 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.9328033E-7).
• BP6: Variant 3-41883906-C-T is Benign according to our data. Variant chr3-41883906-C-T is described in ClinVar as Benign. ClinVar VariationId is 403584.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.823 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017886.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ULK4	NM_017886.4	MANE Select	c.1624G>A	p.Ala542Thr	missense	Exon 17 of 37	NP_060356.2
	ULK4	NM_001322500.2		c.1624G>A	p.Ala542Thr	missense	Exon 17 of 36	NP_001309429.1
	ULK4	NM_001322501.2		c.718G>A	p.Ala240Thr	missense	Exon 16 of 36	NP_001309430.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ULK4	ENST00000301831.9	TSL:2 MANE Select	c.1624G>A	p.Ala542Thr	missense	Exon 17 of 37	ENSP00000301831.4
	ULK4	ENST00000420927.5	TSL:1	c.1624G>A	p.Ala542Thr	missense	Exon 17 of 18	ENSP00000412187.1

Frequencies

GnomAD3 genomes AF: 0.690 AC: 104866 AN: 152048 Hom.: 39481 Cov.: 33

Gnomad AFR AF: 0.357

Gnomad AMI AF: 0.785

Gnomad AMR AF: 0.788

Gnomad ASJ AF: 0.808

Gnomad EAS AF: 0.834

Gnomad SAS AF: 0.811

Gnomad FIN AF: 0.775

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.829

Gnomad OTH AF: 0.709

GnomAD2 exomes AF: 0.796 AC: 198487 AN: 249506 AF XY: 0.801

Gnomad AFR exome AF: 0.351

Gnomad AMR exome AF: 0.860

Gnomad ASJ exome AF: 0.816

Gnomad EAS exome AF: 0.818

Gnomad FIN exome AF: 0.777

Gnomad NFE exome AF: 0.828

Gnomad OTH exome AF: 0.799

GnomAD4 exome AF: 0.820 AC: 1192701 AN: 1454792 Hom.: 493818 Cov.: 42 AF XY: 0.821 AC XY: 594621 AN XY: 724146

African (AFR) AF: 0.335 AC: 11156 AN: 33330

American (AMR) AF: 0.855 AC: 38228 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.812 AC: 21169 AN: 26074

East Asian (EAS) AF: 0.853 AC: 33839 AN: 39674

South Asian (SAS) AF: 0.817 AC: 70373 AN: 86088

European-Finnish (FIN) AF: 0.786 AC: 41996 AN: 53412

Middle Eastern (MID) AF: 0.655 AC: 3770 AN: 5760

European-Non Finnish (NFE) AF: 0.836 AC: 924521 AN: 1105578

Other (OTH) AF: 0.792 AC: 47649 AN: 60172

GnomAD4 genome AF: 0.689 AC: 104900 AN: 152166 Hom.: 39499 Cov.: 33 AF XY: 0.691 AC XY: 51388 AN XY: 74384

African (AFR) AF: 0.357 AC: 14804 AN: 41480

American (AMR) AF: 0.788 AC: 12051 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.808 AC: 2806 AN: 3472

East Asian (EAS) AF: 0.835 AC: 4322 AN: 5178

South Asian (SAS) AF: 0.812 AC: 3920 AN: 4828

European-Finnish (FIN) AF: 0.775 AC: 8214 AN: 10592

Middle Eastern (MID) AF: 0.612 AC: 180 AN: 294

European-Non Finnish (NFE) AF: 0.829 AC: 56385 AN: 68008

Other (OTH) AF: 0.711 AC: 1504 AN: 2114

Alfa AF: 0.787 Hom.: 236847

Bravo AF: 0.677

TwinsUK AF: 0.831 AC: 3080

ALSPAC AF: 0.839 AC: 3235

ESP6500AA AF: 0.376 AC: 1436

ESP6500EA AF: 0.826 AC: 6779

ExAC AF: 0.788 AC: 95231

Asia WGS AF: 0.805 AC: 2802 AN: 3478

EpiCase AF: 0.811

EpiControl AF: 0.814

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.17
DANN	Benign	0.21
DEOGEN2	Benign	0.00023	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.00097	N
LIST_S2	Benign	0.091	T
MetaRNN	Benign	5.9e-7	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.1	N
PhyloP100		-0.012
PrimateAI	Benign	0.35	T
PROVEAN	Benign	2.2	N
REVEL	Benign	0.10
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.037
MPC		0.035
ClinPred		0.00081	T
GERP RS		0.24
Varity_R		0.027
gMVP		0.082
Mutation Taster		=99/1	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: rs1052501; hg19: chr3-41925398; COSMIC: COSV57217932;