3-41918514-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_017886.4(ULK4):c.670A>G(p.Ile224Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.803 in 1,581,668 control chromosomes in the GnomAD database, including 519,508 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.68 (38612 hom., cov: 30)
  • Exomes 𝑓: 0.82 (480896 hom.)
• Consequence: ULK4 NM_017886.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.135

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.0694714E-7).
• BP6: Variant 3-41918514-T-C is Benign according to our data. Variant chr3-41918514-T-C is described in ClinVar as [Benign]. Clinvar id is 403590.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.819 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ULK4	NM_017886.4	c.670A>G	p.Ile224Val	missense_variant	7/37	ENST00000301831.9
ULK4	NM_001322500.2	c.670A>G	p.Ile224Val	missense_variant	7/36
ULK4	NM_001322501.2	c.-161A>G		5_prime_UTR_variant	7/36
ULK4	NR_136342.2	n.806A>G		non_coding_transcript_exon_variant	7/35

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ULK4	ENST00000301831.9	c.670A>G	p.Ile224Val	missense_variant	7/37	2	NM_017886.4	P1
ULK4	ENST00000420927.5	c.670A>G	p.Ile224Val	missense_variant	7/18	1

Frequencies

GnomAD3 genomes AF: 0.680 AC: 102996 AN: 151440 Hom.: 38593 Cov.: 30

Gnomad AFR AF: 0.333

Gnomad AMI AF: 0.783

Gnomad AMR AF: 0.778

Gnomad ASJ AF: 0.804

Gnomad EAS AF: 0.832

Gnomad SAS AF: 0.820

Gnomad FIN AF: 0.775

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.825

Gnomad OTH AF: 0.697

GnomAD3 exomes AF: 0.787 AC: 180629 AN: 229482 Hom.: 73091 AF XY: 0.793 AC XY: 98796 AN XY: 124516

Gnomad AFR exome AF: 0.323

Gnomad AMR exome AF: 0.851

Gnomad ASJ exome AF: 0.813

Gnomad EAS exome AF: 0.814

Gnomad SAS exome AF: 0.822

Gnomad FIN exome AF: 0.776

Gnomad NFE exome AF: 0.822

Gnomad OTH exome AF: 0.790

GnomAD4 exome AF: 0.816 AC: 1166405 AN: 1430112 Hom.: 480896 Cov.: 30 AF XY: 0.817 AC XY: 580337 AN XY: 710256

Gnomad4 AFR exome AF: 0.307

Gnomad4 AMR exome AF: 0.845

Gnomad4 ASJ exome AF: 0.809

Gnomad4 EAS exome AF: 0.852

Gnomad4 SAS exome AF: 0.821

Gnomad4 FIN exome AF: 0.786

Gnomad4 NFE exome AF: 0.832

Gnomad4 OTH exome AF: 0.787

GnomAD4 genome AF: 0.680 AC: 103031 AN: 151556 Hom.: 38612 Cov.: 30 AF XY: 0.681 AC XY: 50409 AN XY: 73976

Gnomad4 AFR AF: 0.332

Gnomad4 AMR AF: 0.778

Gnomad4 ASJ AF: 0.804

Gnomad4 EAS AF: 0.832

Gnomad4 SAS AF: 0.821

Gnomad4 FIN AF: 0.775

Gnomad4 NFE AF: 0.825

Gnomad4 OTH AF: 0.699

Alfa AF: 0.798 Hom.: 109299

Bravo AF: 0.665

TwinsUK AF: 0.827 AC: 3066

ALSPAC AF: 0.835 AC: 3219

ESP6500AA AF: 0.344 AC: 1249

ESP6500EA AF: 0.822 AC: 6702

ExAC AF: 0.785 AC: 94736

Asia WGS AF: 0.805 AC: 2802 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	1.3
Dann	Benign	0.36
DEOGEN2	Benign	0.0013	T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.39	T;T
MetaRNN	Benign	6.1e-7	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.76	N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.41	N;N
REVEL	Benign	0.048
Sift	Benign	0.54	T;T
Sift4G	Benign	0.56	T;T
Polyphen		0.0	B;.
Vest4		0.015
MPC		0.032
ClinPred		0.0018	T
GERP RS		-5.9
Varity_R		0.064
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1716975; hg19: chr3-41960006; COSMIC: COSV57216978; COSMIC: COSV57216978;