3-41883906-C-T

Position:

• chr3-41883906-C-T

Variant summary

Our verdict is Benign. Variant got -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. 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 0.69 (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

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 -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ULK4	NM_017886.4	c.1624G>A	p.Ala542Thr	missense_variant	17/37	ENST00000301831.9	NP_060356.2
ULK4	NM_001322500.2	c.1624G>A	p.Ala542Thr	missense_variant	17/36		NP_001309429.1
ULK4	NM_001322501.2	c.718G>A	p.Ala240Thr	missense_variant	16/36		NP_001309430.1
ULK4	NR_136342.2	n.1690G>A		non_coding_transcript_exon_variant	16/35

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ULK4	ENST00000301831.9	c.1624G>A	p.Ala542Thr	missense_variant	17/37	2	NM_017886.4	ENSP00000301831	P1
ULK4	ENST00000420927.5	c.1624G>A	p.Ala542Thr	missense_variant	17/18	1		ENSP00000412187

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

GnomAD3 exomes AF: 0.796 AC: 198487 AN: 249506 Hom.: 80860 AF XY: 0.801 AC XY: 108413 AN XY: 135370

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 SAS exome AF: 0.820

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

Gnomad4 AFR exome AF: 0.335

Gnomad4 AMR exome AF: 0.855

Gnomad4 ASJ exome AF: 0.812

Gnomad4 EAS exome AF: 0.853

Gnomad4 SAS exome AF: 0.817

Gnomad4 FIN exome AF: 0.786

Gnomad4 NFE exome AF: 0.836

Gnomad4 OTH exome AF: 0.792

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

Gnomad4 AFR AF: 0.357

Gnomad4 AMR AF: 0.788

Gnomad4 ASJ AF: 0.808

Gnomad4 EAS AF: 0.835

Gnomad4 SAS AF: 0.812

Gnomad4 FIN AF: 0.775

Gnomad4 NFE AF: 0.829

Gnomad4 OTH AF: 0.711

Alfa AF: 0.802 Hom.: 126700

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

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 -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

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;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.00097	N
LIST_S2	Benign	0.091	T;T
MetaRNN	Benign	5.9e-7	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.1	N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	2.2	N;N
REVEL	Benign	0.10
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;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

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: rs1052501; hg19: chr3-41925398; COSMIC: COSV57217932;