rs55656741

chr5-31515550-G-Achr5-31515550-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BA1

The NM_001382508.1(DROSHA):c.962C>T(p.Ser321Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.46 in 1,548,624 control chromosomes in the GnomAD database, including 172,082 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.36 (12285 hom., cov: 33)
  • Exomes 𝑓: 0.47 (159797 hom.)
• Consequence: DROSHA NM_001382508.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.960

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 -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, DROSHA
• BP4: Computational evidence support a benign effect (MetaRNN=4.9096346E-4).
• BP6: Variant 5-31515550-G-A is Benign according to our data. Variant chr5-31515550-G-A is described in ClinVar as [Benign]. Clinvar id is 3059023.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.493 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DROSHA	NM_001382508.1	c.962C>T	p.Ser321Leu	missense_variant	7/36	ENST00000344624.8
DROSHA	NM_013235.5	c.962C>T	p.Ser321Leu	missense_variant	6/35
DROSHA	NM_001100412.2	c.948-331C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DROSHA	ENST00000344624.8	c.962C>T	p.Ser321Leu	missense_variant	7/36	5	NM_001382508.1	P4

Frequencies

GnomAD3 genomes AF: 0.362 AC: 54972 AN: 151998 Hom.: 12286 Cov.: 33

Gnomad AFR AF: 0.0935

Gnomad AMI AF: 0.520

Gnomad AMR AF: 0.409

Gnomad ASJ AF: 0.399

Gnomad EAS AF: 0.197

Gnomad SAS AF: 0.477

Gnomad FIN AF: 0.466

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.498

Gnomad OTH AF: 0.384

GnomAD3 exomes AF: 0.432 AC: 66716 AN: 154384 Hom.: 15445 AF XY: 0.439 AC XY: 35897 AN XY: 81730

Gnomad AFR exome AF: 0.0875

Gnomad AMR exome AF: 0.441

Gnomad ASJ exome AF: 0.404

Gnomad EAS exome AF: 0.201

Gnomad SAS exome AF: 0.480

Gnomad FIN exome AF: 0.473

Gnomad NFE exome AF: 0.492

Gnomad OTH exome AF: 0.437

GnomAD4 exome AF: 0.470 AC: 657025 AN: 1396508 Hom.: 159797 Cov.: 34 AF XY: 0.471 AC XY: 324779 AN XY: 688940

Gnomad4 AFR exome AF: 0.0803

Gnomad4 AMR exome AF: 0.430

Gnomad4 ASJ exome AF: 0.407

Gnomad4 EAS exome AF: 0.190

Gnomad4 SAS exome AF: 0.477

Gnomad4 FIN exome AF: 0.472

Gnomad4 NFE exome AF: 0.496

Gnomad4 OTH exome AF: 0.434

GnomAD4 genome AF: 0.361 AC: 54975 AN: 152116 Hom.: 12285 Cov.: 33 AF XY: 0.363 AC XY: 27009 AN XY: 74346

Gnomad4 AFR AF: 0.0933

Gnomad4 AMR AF: 0.409

Gnomad4 ASJ AF: 0.399

Gnomad4 EAS AF: 0.198

Gnomad4 SAS AF: 0.479

Gnomad4 FIN AF: 0.466

Gnomad4 NFE AF: 0.498

Gnomad4 OTH AF: 0.382

Alfa AF: 0.455 Hom.: 26265

Bravo AF: 0.343

TwinsUK AF: 0.497 AC: 1844

ALSPAC AF: 0.489 AC: 1884

ESP6500AA AF: 0.104 AC: 196

ESP6500EA AF: 0.491 AC: 2054

ExAC AF: 0.392 AC: 10229

Asia WGS AF: 0.303 AC: 1058 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
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	18
Dann	Benign	0.82
DEOGEN2	Benign	0.12	T;T;.
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.17	N
MetaRNN	Benign	0.00049	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.34	N;N;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.65	N;N;N
REVEL	Benign	0.040
Sift	Uncertain	0.017	D;D;T
Sift4G	Benign	0.63	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.17
MPC		0.10
ClinPred		0.0052	T
GERP RS		2.0
Varity_R		0.048
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs55656741; hg19: chr5-31515657; COSMIC: COSV60772644;