5-31424426-C-G

Position:

• chr5-31424426-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_001382508.1(DROSHA):​c.3261+1G>C variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DROSHA NM_001382508.1 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 6.55

Genes affected

DROSHA (HGNC:17904): (drosha ribonuclease III) This gene encodes a ribonuclease (RNase) III double-stranded RNA-specific ribonuclease and subunit of the microprocessor protein complex, which catalyzes the initial processing step of microRNA (miRNA) synthesis. The encoded protein cleaves the stem loop structure from the primary microRNA (pri-miRNA) in the nucleus, yielding the precursor miRNA (pre-miRNA), which is then exported to the cytoplasm for further processing. In a human cell line lacking a functional copy of this gene, canonical miRNA synthesis is reduced. Somatic mutations in this gene have been observed in human patients with kidney cancer. [provided by RefSeq, Sep 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.010666667 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.3, offset of 24, new splice context is: gcaGTgagc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-31424426-C-G is Pathogenic according to our data. Variant chr5-31424426-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 3393488.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DROSHA	NM_001382508.1	c.3261+1G>C		splice_donor_variant, intron_variant		ENST00000344624.8	NP_001369437.1
DROSHA	NM_013235.5	c.3261+1G>C		splice_donor_variant, intron_variant			NP_037367.3
DROSHA	NM_001100412.2	c.3150+1G>C		splice_donor_variant, intron_variant			NP_001093882.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DROSHA	ENST00000344624.8	c.3261+1G>C		splice_donor_variant, intron_variant		5	NM_001382508.1	ENSP00000339845.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Pineoblastoma Pathogenic:1 Other:1

-, no assertion criteria provided	clinical testing	Center for Precision Oncology and Cancer Prevention, Roswell Park Comprehensive Cancer Center	Nov 22, 2024	This variant was the second hit in a two-hit mechanism of pineoblastoma where the individual also carried a germline pathogenic DROSHA variant. -
Pathogenic, no assertion criteria provided	clinical testing	Center for Precision Oncology and Cancer Prevention, Roswell Park Comprehensive Cancer Center	Nov 22, 2024	Germline analysis revealed a DROSHA c.3261+1G>C splicing variant resulting in out-of-frame exon skipping with loss of the donor site at exon 27 (SpliceAI Delta Score=0.95). Tumor analysis revealed LOH of this variant, with a variant allele fraction in the tumor of 1.00, confirming biallelic inactivation of DROSHA. It was found in an 11-year-old girl with pineoblastoma. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.95		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-31424533;