5-31408606-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001382508.1(DROSHA):c.3854+450A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 158,422 control chromosomes in the GnomAD database, including 2,131 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.16 (2065 hom., cov: 32)
  • Exomes 𝑓: 0.13 (66 hom.)
• Consequence: DROSHA NM_001382508.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.377

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.282 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DROSHA	NM_001382508.1	c.3854+450A>G		intron_variant		ENST00000344624.8
DROSHA	NM_001100412.2	c.3743+450A>G		intron_variant
DROSHA	NM_013235.5	c.3854+450A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DROSHA	ENST00000344624.8	c.3854+450A>G		intron_variant		5	NM_001382508.1	P4
DROSHA	ENST00000511367.6	c.3854+450A>G		intron_variant		1		P4
DROSHA	ENST00000513349.5	c.3743+450A>G		intron_variant		1		A1
DROSHA	ENST00000511778.5	n.970+450A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23857 AN: 151990 Hom.: 2060 Cov.: 32

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.265

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.294

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.159

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.163

GnomAD4 exome AF: 0.126 AC: 793 AN: 6314 Hom.: 66 AF XY: 0.129 AC XY: 422 AN XY: 3272

Gnomad4 AFR exome AF: 0.118

Gnomad4 AMR exome AF: 0.149

Gnomad4 ASJ exome AF: 0.0435

Gnomad4 EAS exome AF: 0.244

Gnomad4 SAS exome AF: 0.148

Gnomad4 FIN exome AF: 0.0577

Gnomad4 NFE exome AF: 0.109

Gnomad4 OTH exome AF: 0.121

GnomAD4 genome AF: 0.157 AC: 23887 AN: 152108 Hom.: 2065 Cov.: 32 AF XY: 0.160 AC XY: 11911 AN XY: 74358

Gnomad4 AFR AF: 0.135

Gnomad4 AMR AF: 0.208

Gnomad4 ASJ AF: 0.210

Gnomad4 EAS AF: 0.294

Gnomad4 SAS AF: 0.215

Gnomad4 FIN AF: 0.148

Gnomad4 NFE AF: 0.142

Gnomad4 OTH AF: 0.167

Alfa AF: 0.0955 Hom.: 171

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	4.6
Dann	Benign	0.63

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: rs615435; hg19: chr5-31408713;