NM_001382508.1:c.3548delA

Variant names:

• chr5-31410864-AT-A
• NM_001382508.1:c.3548delA

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_001382508.1(DROSHA):​c.3548delA​(p.Asn1183IlefsTer8) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DROSHA NM_001382508.1 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.56

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-31410864-AT-A is Pathogenic according to our data. Variant chr5-31410864-AT-A is described in ClinVar as [Pathogenic]. Clinvar id is 3393489.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DROSHA	NM_001382508.1	c.3548delA	p.Asn1183IlefsTer8	frameshift_variant	Exon 31 of 36	ENST00000344624.8	NP_001369437.1
DROSHA	NM_013235.5	c.3548delA	p.Asn1183IlefsTer8	frameshift_variant	Exon 30 of 35		NP_037367.3
DROSHA	NM_001100412.2	c.3437delA	p.Asn1146IlefsTer8	frameshift_variant	Exon 30 of 35		NP_001093882.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DROSHA	ENST00000344624.8	c.3548delA	p.Asn1183IlefsTer8	frameshift_variant	Exon 31 of 36	5	NM_001382508.1	ENSP00000339845.3
DROSHA	ENST00000511367.6	c.3548delA	p.Asn1183IlefsTer8	frameshift_variant	Exon 30 of 35	1		ENSP00000425979.2
DROSHA	ENST00000513349.5	c.3437delA	p.Asn1146IlefsTer8	frameshift_variant	Exon 30 of 35	1		ENSP00000424161.1
DROSHA	ENST00000511778.5	n.664delA		non_coding_transcript_exon_variant	Exon 3 of 8	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Pineoblastoma Pathogenic:1

Nov 22, 2024

Center for Precision Oncology and Cancer Prevention, Roswell Park Comprehensive Cancer Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This was found in a 15-year-old girl with pineoblastoma with VAF=0.48. -

Computational scores

Source: dbNSFP v4.3

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-31410971;