15-74840645-C-T

Position:

• chr15-74840645-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001099436.4(ULK3):​c.470-4G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000963 in 1,556,938 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (27 hom.)
• Consequence: ULK3 NM_001099436.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0005280
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.59

Genes affected

ULK3 (HGNC:19703): (unc-51 like kinase 3) Enables protein serine/threonine kinase activity. Involved in several processes, including fibroblast activation; protein autophosphorylation; and regulation of smoothened signaling pathway. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

MIR6882 (HGNC:49928): (microRNA 6882) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 15-74840645-C-T is Benign according to our data. Variant chr15-74840645-C-T is described in ClinVar as [Benign]. Clinvar id is 740145.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00101 (1413/1404642) while in subpopulation SAS AF= 0.0173 (1324/76354). AF 95% confidence interval is 0.0166. There are 27 homozygotes in gnomad4_exome. There are 990 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ULK3	NM_001099436.4	c.470-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000440863.7	NP_001092906.3
MIR6882	NR_106942.1	n.63G>A		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ULK3	ENST00000440863.7	c.470-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2	NM_001099436.4	ENSP00000400312	A1
MIR6882	ENST00000619233.1	n.63G>A		mature_miRNA_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.000565 AC: 86 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0178

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00185 AC: 367 AN: 198554 Hom.: 4 AF XY: 0.00221 AC XY: 235 AN XY: 106498

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000760

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000121

Gnomad SAS exome AF: 0.0179

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000430

Gnomad OTH exome AF: 0.00152

GnomAD4 exome AF: 0.00101 AC: 1413 AN: 1404642 Hom.: 27 Cov.: 32 AF XY: 0.00143 AC XY: 990 AN XY: 693564

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000560

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000764

Gnomad4 SAS exome AF: 0.0173

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000120

Gnomad4 OTH exome AF: 0.00121

GnomAD4 genome AF: 0.000565 AC: 86 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.000806 AC XY: 60 AN XY: 74458

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0178

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000342 Hom.: 0

Bravo AF: 0.000140

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	13
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00053
dbscSNV1_RF	Benign	0.064
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: rs531063819; hg19: chr15-75132986; COSMIC: COSV51513587; COSMIC: COSV51513587;