3-41897008-G-C

Variant names:

• chr3-41897008-G-C
• rs1717005
• NM_017886.4:c.1349-5C>G

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.1349-5C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.984 in 1,604,058 control chromosomes in the GnomAD database, including 779,138 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.93 (66384 hom., cov: 31)
  • Exomes 𝑓: 0.99 (712754 hom.)
• Consequence: ULK4 NM_017886.4 splice_region, intron
• Scores: Splicing: ADA: 0.0002944
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.97
• Publications: 7 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 (BayesDel_noAF=-0.87).
• BP6: Variant 3-41897008-G-C is Benign according to our data. Variant chr3-41897008-G-C is described in ClinVar as Benign. ClinVar VariationId is 403587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.991 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ULK4	NM_017886.4	c.1349-5C>G		splice_region_variant, intron_variant	Intron 14 of 36	ENST00000301831.9	NP_060356.2
ULK4	NM_001322500.2	c.1349-5C>G		splice_region_variant, intron_variant	Intron 14 of 35		NP_001309429.1
ULK4	NM_001322501.2	c.443-5C>G		splice_region_variant, intron_variant	Intron 13 of 35		NP_001309430.1
ULK4	NR_136342.2	n.1415-5C>G		splice_region_variant, intron_variant	Intron 13 of 34

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ULK4	ENST00000301831.9	c.1349-5C>G		splice_region_variant, intron_variant	Intron 14 of 36	2	NM_017886.4	ENSP00000301831.4
ULK4	ENST00000420927.5	c.1349-5C>G		splice_region_variant, intron_variant	Intron 14 of 17	1		ENSP00000412187.1

Frequencies

GnomAD3 genomes AF: 0.928 AC: 141195 AN: 152112 Hom.: 66356 Cov.: 31

Gnomad AFR AF: 0.760

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.964

Gnomad ASJ AF: 0.979

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 0.999

Gnomad MID AF: 0.949

Gnomad NFE AF: 0.997

Gnomad OTH AF: 0.944

GnomAD2 exomes AF: 0.979 AC: 237951 AN: 243012 AF XY: 0.984

Gnomad AFR exome AF: 0.753

Gnomad AMR exome AF: 0.981

Gnomad ASJ exome AF: 0.982

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.999

Gnomad NFE exome AF: 0.996

Gnomad OTH exome AF: 0.983

GnomAD4 exome AF: 0.990 AC: 1437410 AN: 1451828 Hom.: 712754 Cov.: 29 AF XY: 0.991 AC XY: 715964 AN XY: 722486

African (AFR) AF: 0.740 AC: 24333 AN: 32898

American (AMR) AF: 0.980 AC: 42218 AN: 43076

Ashkenazi Jewish (ASJ) AF: 0.981 AC: 25358 AN: 25850

East Asian (EAS) AF: 1.00 AC: 39605 AN: 39606

South Asian (SAS) AF: 0.998 AC: 85653 AN: 85790

European-Finnish (FIN) AF: 0.999 AC: 51687 AN: 51744

Middle Eastern (MID) AF: 0.942 AC: 5375 AN: 5708

European-Non Finnish (NFE) AF: 0.998 AC: 1104495 AN: 1107160

Other (OTH) AF: 0.978 AC: 58686 AN: 59996

GnomAD4 genome AF: 0.928 AC: 141269 AN: 152230 Hom.: 66384 Cov.: 31 AF XY: 0.930 AC XY: 69221 AN XY: 74438

African (AFR) AF: 0.760 AC: 31513 AN: 41486

American (AMR) AF: 0.964 AC: 14739 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.979 AC: 3400 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5184 AN: 5184

South Asian (SAS) AF: 0.999 AC: 4818 AN: 4824

European-Finnish (FIN) AF: 0.999 AC: 10608 AN: 10622

Middle Eastern (MID) AF: 0.946 AC: 278 AN: 294

European-Non Finnish (NFE) AF: 0.997 AC: 67825 AN: 68036

Other (OTH) AF: 0.945 AC: 1992 AN: 2108

Alfa AF: 0.977 Hom.: 23488

Bravo AF: 0.917

Asia WGS AF: 0.975 AC: 3391 AN: 3478

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.54
DANN	Benign	0.64
PhyloP100		-2.0
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00029
dbscSNV1_RF	Benign	0.048
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: rs1717005; hg19: chr3-41938500;