5-31408606-T-G

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>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0725 in 158,446 control chromosomes in the GnomAD database, including 1,409 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 0.075 (1406 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (3 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=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0753 AC: 11439 AN: 151998 Hom.: 1405 Cov.: 32

Gnomad AFR AF: 0.261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0268

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.0627

GnomAD4 exome AF: 0.00521 AC: 33 AN: 6330 Hom.: 3 AF XY: 0.00550 AC XY: 18 AN XY: 3274

Gnomad4 AFR exome AF: 0.206

Gnomad4 AMR exome AF: 0.0130

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00141

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000561

Gnomad4 OTH exome AF: 0.0141

GnomAD4 genome AF: 0.0753 AC: 11460 AN: 152116 Hom.: 1406 Cov.: 32 AF XY: 0.0725 AC XY: 5393 AN XY: 74368

Gnomad4 AFR AF: 0.261

Gnomad4 AMR AF: 0.0266

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00126

Gnomad4 OTH AF: 0.0620

Alfa AF: 0.0000413 Hom.: 171

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	3.9
Dann	Benign	0.67

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;