rs4973986

Variant names:

• chr3-41800224-A-C
• rs4973986
• NM_017886.4:c.1918T>G

Your query was ambiguous. Multiple possible variants found:

• chr3-41800224-A-C
• chr3-41800224-A-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.1918T>G​(p.Ser640Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.844 in 1,613,390 control chromosomes in the GnomAD database, including 576,227 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.87 (58179 hom., cov: 31)
  • Exomes 𝑓: 0.84 (518048 hom.)
• Consequence: ULK4 NM_017886.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.21
• Publications: 33 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 (MetaRNN=6.3316344E-7).
• BP6: Variant 3-41800224-A-C is Benign according to our data. Variant chr3-41800224-A-C is described in ClinVar as Benign. ClinVar VariationId is 403583.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.962 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.1918T>G	p.Ser640Ala	missense	Exon 20 of 37	NP_060356.2
	ULK4	NM_001322500.2		c.1918T>G	p.Ser640Ala	missense	Exon 20 of 36	NP_001309429.1
	ULK4	NM_001322501.2		c.1012T>G	p.Ser338Ala	missense	Exon 19 of 36	NP_001309430.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ULK4	ENST00000301831.9	TSL:2 MANE Select	c.1918T>G	p.Ser640Ala	missense	Exon 20 of 37	ENSP00000301831.4
	ULK4	ENST00000460406.1	TSL:2	n.399T>G		non_coding_transcript_exon	Exon 5 of 5

Frequencies

GnomAD3 genomes AF: 0.871 AC: 132422 AN: 151980 Hom.: 58112 Cov.: 31

Gnomad AFR AF: 0.970

Gnomad AMI AF: 0.637

Gnomad AMR AF: 0.898

Gnomad ASJ AF: 0.889

Gnomad EAS AF: 0.780

Gnomad SAS AF: 0.846

Gnomad FIN AF: 0.769

Gnomad MID AF: 0.911

Gnomad NFE AF: 0.832

Gnomad OTH AF: 0.869

GnomAD2 exomes AF: 0.851 AC: 211889 AN: 249016 AF XY: 0.846

Gnomad AFR exome AF: 0.972

Gnomad AMR exome AF: 0.930

Gnomad ASJ exome AF: 0.892

Gnomad EAS exome AF: 0.780

Gnomad FIN exome AF: 0.775

Gnomad NFE exome AF: 0.835

Gnomad OTH exome AF: 0.847

GnomAD4 exome AF: 0.841 AC: 1229387 AN: 1461292 Hom.: 518048 Cov.: 45 AF XY: 0.841 AC XY: 611221 AN XY: 726990

African (AFR) AF: 0.976 AC: 32650 AN: 33470

American (AMR) AF: 0.925 AC: 41327 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.894 AC: 23353 AN: 26126

East Asian (EAS) AF: 0.802 AC: 31806 AN: 39660

South Asian (SAS) AF: 0.842 AC: 72601 AN: 86184

European-Finnish (FIN) AF: 0.780 AC: 41685 AN: 53410

Middle Eastern (MID) AF: 0.892 AC: 5139 AN: 5758

European-Non Finnish (NFE) AF: 0.836 AC: 929798 AN: 1111670

Other (OTH) AF: 0.845 AC: 51028 AN: 60360

GnomAD4 genome AF: 0.871 AC: 132549 AN: 152098 Hom.: 58179 Cov.: 31 AF XY: 0.868 AC XY: 64517 AN XY: 74334

African (AFR) AF: 0.970 AC: 40288 AN: 41530

American (AMR) AF: 0.898 AC: 13710 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.889 AC: 3083 AN: 3466

East Asian (EAS) AF: 0.780 AC: 4033 AN: 5172

South Asian (SAS) AF: 0.846 AC: 4073 AN: 4814

European-Finnish (FIN) AF: 0.769 AC: 8109 AN: 10550

Middle Eastern (MID) AF: 0.918 AC: 270 AN: 294

European-Non Finnish (NFE) AF: 0.832 AC: 56572 AN: 67986

Other (OTH) AF: 0.869 AC: 1834 AN: 2110

Alfa AF: 0.854 Hom.: 167417

Bravo AF: 0.886

TwinsUK AF: 0.847 AC: 3139

ALSPAC AF: 0.833 AC: 3212

ESP6500AA AF: 0.970 AC: 3583

ESP6500EA AF: 0.835 AC: 6845

ExAC AF: 0.851 AC: 102810

Asia WGS AF: 0.830 AC: 2888 AN: 3478

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
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	17
DANN	Benign	0.45
DEOGEN2	Benign	0.00031	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.050	T
MetaRNN	Benign	6.3e-7	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.5	N
PhyloP100		2.2
PrimateAI	Benign	0.46	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.19
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.019
MPC		0.032
ClinPred		0.0079	T
GERP RS		5.3
Varity_R		0.078
gMVP		0.36
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4973986; hg19: chr3-41841716; COSMIC: COSV57206179;