3-41398183-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017886.4(ULK4):c.3574C>T(p.Pro1192Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,314 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ULK4 NM_017886.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.12

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33743462).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ULK4	NM_017886.4	c.3574C>T	p.Pro1192Ser	missense_variant	35/37	ENST00000301831.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ULK4	ENST00000301831.9	c.3574C>T	p.Pro1192Ser	missense_variant	35/37	2	NM_017886.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 249030 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135086

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461314 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726968

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 11, 2022

The c.3574C>T (p.P1192S) alteration is located in exon 35 (coding exon 34) of the ULK4 gene. This alteration results from a C to T substitution at nucleotide position 3574, causing the proline (P) at amino acid position 1192 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0029	T
Eigen	Benign	0.060
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	0.98	N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.093
Sift	Benign	0.035	D
Sift4G	Benign	0.24	T
Polyphen		0.48	P
Vest4		0.59
MutPred		0.29		Gain of relative solvent accessibility (P = 0.0166);
MVP		0.62
MPC		0.043
ClinPred		0.33	T
GERP RS		4.8
Varity_R		0.081
gMVP		0.28

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: rs754228128; hg19: chr3-41439674;