3-41915974-T-G

Variant names:

• chr3-41915974-T-G
• rs1716698
• NM_017886.4:c.803+3A>C

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.803+3A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.806 in 1,583,686 control chromosomes in the GnomAD database, including 524,032 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (39029 hom., cov: 32)
  • Exomes 𝑓: 0.82 (485003 hom.)
• Consequence: ULK4 NM_017886.4 splice_region, intron
• Scores: Splicing: ADA: 0.2529
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.472
• Publications: 17 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=-0.81).
• BP6: Variant 3-41915974-T-G is Benign according to our data. Variant chr3-41915974-T-G is described in ClinVar as Benign. ClinVar VariationId is 403589.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.803+3A>C		splice_region intron	N/A	NP_060356.2
	ULK4	NM_001322500.2		c.803+3A>C		splice_region intron	N/A	NP_001309429.1
	ULK4	NM_001322501.2		c.-104+2483A>C		intron	N/A	NP_001309430.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ULK4	ENST00000301831.9	TSL:2 MANE Select	c.803+3A>C		splice_region intron	N/A	ENSP00000301831.4
	ULK4	ENST00000420927.5	TSL:1	c.803+3A>C		splice_region intron	N/A	ENSP00000412187.1
	ULK4	ENST00000951851.1		c.803+3A>C		splice_region intron	N/A	ENSP00000621910.1

Frequencies

GnomAD3 genomes AF: 0.682 AC: 103660 AN: 151916 Hom.: 39013 Cov.: 32

Gnomad AFR AF: 0.334

Gnomad AMI AF: 0.784

Gnomad AMR AF: 0.782

Gnomad ASJ AF: 0.808

Gnomad EAS AF: 0.834

Gnomad SAS AF: 0.819

Gnomad FIN AF: 0.775

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.828

Gnomad OTH AF: 0.701

GnomAD2 exomes AF: 0.789 AC: 179459 AN: 227328 AF XY: 0.796

Gnomad AFR exome AF: 0.329

Gnomad AMR exome AF: 0.852

Gnomad ASJ exome AF: 0.817

Gnomad EAS exome AF: 0.819

Gnomad FIN exome AF: 0.777

Gnomad NFE exome AF: 0.826

Gnomad OTH exome AF: 0.792

GnomAD4 exome AF: 0.819 AC: 1172292 AN: 1431652 Hom.: 485003 Cov.: 31 AF XY: 0.820 AC XY: 584345 AN XY: 712476

African (AFR) AF: 0.309 AC: 9850 AN: 31878

American (AMR) AF: 0.847 AC: 30576 AN: 36082

Ashkenazi Jewish (ASJ) AF: 0.812 AC: 20717 AN: 25504

East Asian (EAS) AF: 0.853 AC: 33382 AN: 39148

South Asian (SAS) AF: 0.821 AC: 65819 AN: 80128

European-Finnish (FIN) AF: 0.786 AC: 41867 AN: 53256

Middle Eastern (MID) AF: 0.650 AC: 3702 AN: 5698

European-Non Finnish (NFE) AF: 0.835 AC: 919656 AN: 1100798

Other (OTH) AF: 0.790 AC: 46723 AN: 59160

GnomAD4 genome AF: 0.682 AC: 103692 AN: 152034 Hom.: 39029 Cov.: 32 AF XY: 0.684 AC XY: 50811 AN XY: 74314

African (AFR) AF: 0.333 AC: 13799 AN: 41436

American (AMR) AF: 0.783 AC: 11961 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.808 AC: 2805 AN: 3470

East Asian (EAS) AF: 0.834 AC: 4309 AN: 5168

South Asian (SAS) AF: 0.819 AC: 3948 AN: 4818

European-Finnish (FIN) AF: 0.775 AC: 8166 AN: 10542

Middle Eastern (MID) AF: 0.609 AC: 179 AN: 294

European-Non Finnish (NFE) AF: 0.828 AC: 56328 AN: 68000

Other (OTH) AF: 0.702 AC: 1482 AN: 2110

Alfa AF: 0.754 Hom.: 27321

Bravo AF: 0.668

Asia WGS AF: 0.803 AC: 2781 AN: 3464

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.011
DANN	Benign	0.63
PhyloP100		0.47
Mutation Taster		=76/24	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.25
dbscSNV1_RF	Benign	0.18
SpliceAI score (max)		0.92		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.92		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1716698; hg19: chr3-41957466;