chr3-41800224-A-C

Position:

• chr3-41800224-A-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.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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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 (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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ULK4	NM_017886.4	c.1918T>G	p.Ser640Ala	missense_variant	20/37	ENST00000301831.9	NP_060356.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ULK4	ENST00000301831.9	c.1918T>G	p.Ser640Ala	missense_variant	20/37	2	NM_017886.4	ENSP00000301831	P1
ULK4	ENST00000460406.1	n.399T>G		non_coding_transcript_exon_variant	5/5	2

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

GnomAD3 exomes AF: 0.851 AC: 211889 AN: 249016 Hom.: 90528 AF XY: 0.846 AC XY: 114362 AN XY: 135110

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 SAS exome AF: 0.843

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

Gnomad4 AFR exome AF: 0.976

Gnomad4 AMR exome AF: 0.925

Gnomad4 ASJ exome AF: 0.894

Gnomad4 EAS exome AF: 0.802

Gnomad4 SAS exome AF: 0.842

Gnomad4 FIN exome AF: 0.780

Gnomad4 NFE exome AF: 0.836

Gnomad4 OTH exome AF: 0.845

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

Gnomad4 AFR AF: 0.970

Gnomad4 AMR AF: 0.898

Gnomad4 ASJ AF: 0.889

Gnomad4 EAS AF: 0.780

Gnomad4 SAS AF: 0.846

Gnomad4 FIN AF: 0.769

Gnomad4 NFE AF: 0.832

Gnomad4 OTH AF: 0.869

Alfa AF: 0.847 Hom.: 107677

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

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

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	P
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

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