5-31435780-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001382508.1(DROSHA):c.3027T>C(p.Leu1009=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0047 in 1,613,836 control chromosomes in the GnomAD database, including 280 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (144 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (136 hom.)
• Consequence: DROSHA NM_001382508.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.221

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 5-31435780-A-G is Benign according to our data. Variant chr5-31435780-A-G is described in ClinVar as [Benign]. Clinvar id is 782448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.221 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.078 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DROSHA	NM_001382508.1	c.3027T>C	p.Leu1009=	synonymous_variant	25/36	ENST00000344624.8
DROSHA	NM_013235.5	c.3027T>C	p.Leu1009=	synonymous_variant	24/35
DROSHA	NM_001100412.2	c.2916T>C	p.Leu972=	synonymous_variant	24/35

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DROSHA	ENST00000344624.8	c.3027T>C	p.Leu1009=	synonymous_variant	25/36	5	NM_001382508.1	P4
DROSHA	ENST00000511367.6	c.3027T>C	p.Leu1009=	synonymous_variant	24/35	1		P4
DROSHA	ENST00000513349.5	c.2916T>C	p.Leu972=	synonymous_variant	24/35	1		A1
DROSHA	ENST00000504133.5	n.171T>C		non_coding_transcript_exon_variant	2/7	3

Frequencies

GnomAD3 genomes AF: 0.0235 AC: 3580 AN: 152182 Hom.: 144 Cov.: 32

Gnomad AFR AF: 0.0805

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00864

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.0196

GnomAD3 exomes AF: 0.00655 AC: 1632 AN: 249016 Hom.: 52 AF XY: 0.00514 AC XY: 694 AN XY: 135068

Gnomad AFR exome AF: 0.0835

Gnomad AMR exome AF: 0.00504

Gnomad ASJ exome AF: 0.00328

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000589

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000780

Gnomad OTH exome AF: 0.00430

GnomAD4 exome AF: 0.00274 AC: 3998 AN: 1461536 Hom.: 136 Cov.: 30 AF XY: 0.00243 AC XY: 1770 AN XY: 727040

Gnomad4 AFR exome AF: 0.0822

Gnomad4 AMR exome AF: 0.00564

Gnomad4 ASJ exome AF: 0.00321

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000349

Gnomad4 OTH exome AF: 0.00626

GnomAD4 genome AF: 0.0235 AC: 3580 AN: 152300 Hom.: 144 Cov.: 32 AF XY: 0.0229 AC XY: 1706 AN XY: 74468

Gnomad4 AFR AF: 0.0803

Gnomad4 AMR AF: 0.00856

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000676

Gnomad4 OTH AF: 0.0194

Alfa AF: 0.00679 Hom.: 36

Bravo AF: 0.0266

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.00153

EpiControl AF: 0.00178

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 06, 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	-0.55
Cadd	Benign	2.4
Dann	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs10039385; hg19: chr5-31435887;