3-41915974-T-G

Variant names:

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

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.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

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 (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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ULK4	NM_017886.4	c.803+3A>C		splice_region_variant, intron_variant	Intron 8 of 36	ENST00000301831.9	NP_060356.2
ULK4	NM_001322500.2	c.803+3A>C		splice_region_variant, intron_variant	Intron 8 of 35		NP_001309429.1
ULK4	NM_001322501.2	c.-104+2483A>C		intron_variant	Intron 7 of 35		NP_001309430.1
ULK4	NR_136342.2	n.939+3A>C		splice_region_variant, intron_variant	Intron 8 of 34

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ULK4	ENST00000301831.9	c.803+3A>C		splice_region_variant, intron_variant	Intron 8 of 36	2	NM_017886.4	ENSP00000301831.4
ULK4	ENST00000420927.5	c.803+3A>C		splice_region_variant, intron_variant	Intron 8 of 17	1		ENSP00000412187.1

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

GnomAD3 exomes AF: 0.789 AC: 179459 AN: 227328 Hom.: 72816 AF XY: 0.796 AC XY: 98583 AN XY: 123880

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 SAS exome AF: 0.822

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

Gnomad4 AFR exome AF: 0.309

Gnomad4 AMR exome AF: 0.847

Gnomad4 ASJ exome AF: 0.812

Gnomad4 EAS exome AF: 0.853

Gnomad4 SAS exome AF: 0.821

Gnomad4 FIN exome AF: 0.786

Gnomad4 NFE exome AF: 0.835

Gnomad4 OTH exome AF: 0.790

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

Gnomad4 AFR AF: 0.333

Gnomad4 AMR AF: 0.783

Gnomad4 ASJ AF: 0.808

Gnomad4 EAS AF: 0.834

Gnomad4 SAS AF: 0.819

Gnomad4 FIN AF: 0.775

Gnomad4 NFE AF: 0.828

Gnomad4 OTH AF: 0.702

Alfa AF: 0.759 Hom.: 23976

Bravo AF: 0.668

Asia WGS AF: 0.803 AC: 2781 AN: 3464

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	-0.81
CADD	Benign	0.011
DANN	Benign	0.63

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

Publications

LitVar

Other links and lift over

dbSNP: rs1716698; hg19: chr3-41957466;