5-31429466-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001382508.1(DROSHA):c.3216+9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00616 in 1,603,348 control chromosomes in the GnomAD database, including 129 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0059 (117 hom.)
• Consequence: DROSHA NM_001382508.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.507

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 5-31429466-T-C is Benign according to our data. Variant chr5-31429466-T-C is described in ClinVar as [Benign]. Clinvar id is 780954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00845 (1286/152212) while in subpopulation EAS AF= 0.0334 (173/5180). AF 95% confidence interval is 0.0293. There are 12 homozygotes in gnomad4. There are 642 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1285 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DROSHA	NM_001382508.1	c.3216+9A>G		intron_variant		ENST00000344624.8
DROSHA	NM_001100412.2	c.3105+9A>G		intron_variant
DROSHA	NM_013235.5	c.3216+9A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DROSHA	ENST00000344624.8	c.3216+9A>G		intron_variant		5	NM_001382508.1	P4

Frequencies

GnomAD3 genomes AF: 0.00845 AC: 1285 AN: 152094 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00472

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.0335

Gnomad SAS AF: 0.0269

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00378

Gnomad OTH AF: 0.00957

GnomAD3 exomes AF: 0.00903 AC: 2184 AN: 241758 Hom.: 40 AF XY: 0.0101 AC XY: 1325 AN XY: 130888

Gnomad AFR exome AF: 0.0155

Gnomad AMR exome AF: 0.00200

Gnomad ASJ exome AF: 0.00403

Gnomad EAS exome AF: 0.0310

Gnomad SAS exome AF: 0.0296

Gnomad FIN exome AF: 0.000560

Gnomad NFE exome AF: 0.00358

Gnomad OTH exome AF: 0.00888

GnomAD4 exome AF: 0.00592 AC: 8587 AN: 1451136 Hom.: 117 Cov.: 30 AF XY: 0.00667 AC XY: 4815 AN XY: 721368

Gnomad4 AFR exome AF: 0.0158

Gnomad4 AMR exome AF: 0.00230

Gnomad4 ASJ exome AF: 0.00481

Gnomad4 EAS exome AF: 0.0227

Gnomad4 SAS exome AF: 0.0312

Gnomad4 FIN exome AF: 0.000470

Gnomad4 NFE exome AF: 0.00322

Gnomad4 OTH exome AF: 0.00975

GnomAD4 genome AF: 0.00845 AC: 1286 AN: 152212 Hom.: 12 Cov.: 32 AF XY: 0.00863 AC XY: 642 AN XY: 74428

Gnomad4 AFR AF: 0.0146

Gnomad4 AMR AF: 0.00471

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.0334

Gnomad4 SAS AF: 0.0267

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.00378

Gnomad4 OTH AF: 0.00994

Alfa AF: 0.00479 Hom.: 1

Bravo AF: 0.00847

Asia WGS AF: 0.0340 AC: 116 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DROSHA-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 05, 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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	3.2
Dann	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs117987306; hg19: chr5-31429573;