5-31422900-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001382508.1(DROSHA):c.3306A>G(p.Pro1102=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.26 in 1,610,786 control chromosomes in the GnomAD database, including 64,261 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.33 (10126 hom., cov: 32)
  • Exomes 𝑓: 0.25 (54135 hom.)
• Consequence: DROSHA NM_001382508.1 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.487

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 5-31422900-T-C is Benign according to our data. Variant chr5-31422900-T-C is described in ClinVar as [Benign]. Clinvar id is 3060707.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.487 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.652 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DROSHA	NM_001382508.1	c.3306A>G	p.Pro1102=	synonymous_variant	29/36	ENST00000344624.8
DROSHA	NM_013235.5	c.3306A>G	p.Pro1102=	synonymous_variant	28/35
DROSHA	NM_001100412.2	c.3195A>G	p.Pro1065=	synonymous_variant	28/35

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DROSHA	ENST00000344624.8	c.3306A>G	p.Pro1102=	synonymous_variant	29/36	5	NM_001382508.1	P4

Frequencies

GnomAD3 genomes AF: 0.334 AC: 50817 AN: 151982 Hom.: 10096 Cov.: 32

Gnomad AFR AF: 0.515

Gnomad AMI AF: 0.287

Gnomad AMR AF: 0.326

Gnomad ASJ AF: 0.311

Gnomad EAS AF: 0.670

Gnomad SAS AF: 0.378

Gnomad FIN AF: 0.259

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.212

Gnomad OTH AF: 0.318

GnomAD3 exomes AF: 0.310 AC: 75867 AN: 244744 Hom.: 13890 AF XY: 0.305 AC XY: 40517 AN XY: 132696

Gnomad AFR exome AF: 0.518

Gnomad AMR exome AF: 0.343

Gnomad ASJ exome AF: 0.307

Gnomad EAS exome AF: 0.663

Gnomad SAS exome AF: 0.366

Gnomad FIN exome AF: 0.247

Gnomad NFE exome AF: 0.214

Gnomad OTH exome AF: 0.279

GnomAD4 exome AF: 0.252 AC: 367262 AN: 1458686 Hom.: 54135 Cov.: 32 AF XY: 0.254 AC XY: 184062 AN XY: 725436

Gnomad4 AFR exome AF: 0.535

Gnomad4 AMR exome AF: 0.341

Gnomad4 ASJ exome AF: 0.298

Gnomad4 EAS exome AF: 0.708

Gnomad4 SAS exome AF: 0.368

Gnomad4 FIN exome AF: 0.249

Gnomad4 NFE exome AF: 0.211

Gnomad4 OTH exome AF: 0.288

GnomAD4 genome AF: 0.335 AC: 50894 AN: 152100 Hom.: 10126 Cov.: 32 AF XY: 0.340 AC XY: 25241 AN XY: 74346

Gnomad4 AFR AF: 0.515

Gnomad4 AMR AF: 0.326

Gnomad4 ASJ AF: 0.311

Gnomad4 EAS AF: 0.670

Gnomad4 SAS AF: 0.376

Gnomad4 FIN AF: 0.259

Gnomad4 NFE AF: 0.212

Gnomad4 OTH AF: 0.324

Alfa AF: 0.243 Hom.: 5727

Bravo AF: 0.349

Asia WGS AF: 0.534 AC: 1855 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

DROSHA-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 30, 2019

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
Cadd	Benign	2.3
Dann	Benign	0.54

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: rs2287584; hg19: chr5-31423007; COSMIC: COSV60772682;