5-31515550-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.36 ( 12285 hom., cov: 33)

Exomes 𝑓: 0.47 ( 159797 hom. )

Consequence

DROSHA
NM_001382508.1 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.960

Publications

30 publications found

Variant links:

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]

DROSHA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

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 VariationId is 3059023.Status of the report is no_assertion_criteria_provided, 0 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 rank	MANE	Protein	UniProt
DROSHA	NM_001382508.1 link	c.962C>T	p.Ser321Leu	missense_variant	Exon 7 of 36	ENST00000344624.8	NP_001369437.1
DROSHA	NM_013235.5 link	c.962C>T	p.Ser321Leu	missense_variant	Exon 6 of 35		NP_037367.3	Q9NRR4-1
DROSHA	NM_001100412.2 link	c.948-331C>T		intron_variant	Intron 6 of 34		NP_001093882.1	Q9NRR4-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DROSHA	ENST00000344624.8 link	c.962C>T	p.Ser321Leu	missense_variant	Exon 7 of 36	5	NM_001382508.1	ENSP00000339845.3		Q9NRR4-1

Frequencies

GnomAD3 genomes

AF:

0.362

AC:

54972

AN:

151998

Hom.:

12286

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.432

AC:

66716

AN:

154384

AF XY:

0.439

show subpopulations

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 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.:

AF XY:

0.471

AC XY:

324779

AN XY:

688940

show subpopulations

African (AFR)

AF:

0.0803

AC:

2536

AN:

31562

American (AMR)

AF:

0.430

AC:

15340

AN:

35648

Ashkenazi Jewish (ASJ)

AF:

0.407

AC:

10233

AN:

25146

East Asian (EAS)

AF:

0.190

AC:

6787

AN:

35728

South Asian (SAS)

AF:

0.477

AC:

37766

AN:

79094

European-Finnish (FIN)

AF:

0.472

AC:

23244

AN:

49252

Middle Eastern (MID)

AF:

0.374

AC:

2122

AN:

5668

European-Non Finnish (NFE)

AF:

0.496

AC:

533894

AN:

1076508

Other (OTH)

AF:

0.434

AC:

25103

AN:

57902

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

16407

32813

49220

65626

82033

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15544

31088

46632

62176

77720

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.361

AC:

54975

AN:

152116

Hom.:

12285

Cov.:

AF XY:

0.363

AC XY:

27009

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.0933

AC:

3872

AN:

41514

American (AMR)

AF:

0.409

AC:

6255

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.399

AC:

1384

AN:

3470

East Asian (EAS)

AF:

0.198

AC:

1024

AN:

5180

South Asian (SAS)

AF:

0.479

AC:

2310

AN:

4822

European-Finnish (FIN)

AF:

0.466

AC:

4924

AN:

10560

Middle Eastern (MID)

AF:

0.344

AC:

101

AN:

294

European-Non Finnish (NFE)

AF:

0.498

AC:

33823

AN:

67964

Other (OTH)

AF:

0.382

AC:

809

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1610

3219

4829

6438

8048

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

532

1064

1596

2128

2660

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.436

Hom.:

35218

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: no assertion criteria provided

LINK: link

Submissions by phenotype

DROSHA-related disorder

Benign:1

Oct 30, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.12

T;T;.

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.82

.;T;T

MetaRNN

Benign

0.00049

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.34

N;N;.

PhyloP100

0.96

PrimateAI

Benign

0.37

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

GERP RS

2.0

Varity_R

0.048

gMVP

0.35

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over