5-31405728-TAAATA-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_001382508.1(DROSHA):c.3948-10_3948-6del variant causes a splice region, splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.000195 in 1,430,738 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00020 (2 hom.)
• Consequence: DROSHA NM_001382508.1 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.85

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 Benign. Variant got -12 ACMG points.

• BP6: Variant 5-31405728-TAAATA-T is Benign according to our data. Variant chr5-31405728-TAAATA-T is described in ClinVar as [Likely_benign]. Clinvar id is 729434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DROSHA	NM_001382508.1	c.3948-10_3948-6del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000344624.8
DROSHA	NM_001100412.2	c.3837-10_3837-6del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
DROSHA	NM_013235.5	c.3948-10_3948-6del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DROSHA	ENST00000344624.8	c.3948-10_3948-6del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001382508.1	P4

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 27 AN: 147128 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000373

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000201

Gnomad SAS AF: 0.000215

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000149

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000147 AC: 20 AN: 136194 Hom.: 0 AF XY: 0.000179 AC XY: 13 AN XY: 72734

Gnomad AFR exome AF: 0.000491

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000116

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000206

Gnomad OTH exome AF: 0.000552

GnomAD4 exome AF: 0.000196 AC: 251 AN: 1283538 Hom.: 2 AF XY: 0.000181 AC XY: 115 AN XY: 636572

Gnomad4 AFR exome AF: 0.000506

Gnomad4 AMR exome AF: 0.000107

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000291

Gnomad4 SAS exome AF: 0.000244

Gnomad4 FIN exome AF: 0.0000208

Gnomad4 NFE exome AF: 0.000195

Gnomad4 OTH exome AF: 0.000319

GnomAD4 genome AF: 0.000190 AC: 28 AN: 147200 Hom.: 0 Cov.: 31 AF XY: 0.000154 AC XY: 11 AN XY: 71456

Gnomad4 AFR AF: 0.000396

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000202

Gnomad4 SAS AF: 0.000216

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000149

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000214 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DROSHA-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 27, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 15, 2017

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs762124264; hg19: chr5-31405835;