Genetic Variant DROSHA:c.1432+36C>A (chr5-31510999-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001382508.1(DROSHA):c.1432+36C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 1,602,116 control chromosomes in the GnomAD database, including 55,653 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.23 ( 4340 hom., cov: 32)

Exomes 𝑓: 0.26 ( 51313 hom. )

Consequence

DROSHA
NM_001382508.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.413

Publications

11 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.351 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001382508.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DROSHA	NM_001382508.1	MANE Select	c.1432+36C>A	intron	N/A	NP_001369437.1	Q9NRR4-1
DROSHA	NM_013235.5		c.1432+36C>A	intron	N/A	NP_037367.3
DROSHA	NM_001100412.2		c.1321+36C>A	intron	N/A	NP_001093882.1	Q9NRR4-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DROSHA	ENST00000344624.8	TSL:5 MANE Select	c.1432+36C>A	intron	N/A	ENSP00000339845.3	Q9NRR4-1
DROSHA	ENST00000511367.6	TSL:1	c.1432+36C>A	intron	N/A	ENSP00000425979.2	Q9NRR4-1
DROSHA	ENST00000513349.5	TSL:1	c.1321+36C>A	intron	N/A	ENSP00000424161.1	Q9NRR4-4

Frequencies

GnomAD3 genomes

AF:

0.228

AC:

34702

AN:

151948

Hom.:

4342

Cov.:

show subpopulations

Gnomad AFR

AF:

0.128

Gnomad AMI

AF:

0.311

Gnomad AMR

AF:

0.255

Gnomad ASJ

AF:

0.307

Gnomad EAS

AF:

0.364

Gnomad SAS

AF:

0.298

Gnomad FIN

AF:

0.263

Gnomad MID

AF:

0.250

Gnomad NFE

AF:

0.257

Gnomad OTH

AF:

0.230

GnomAD2 exomes

AF:

0.267

AC:

64016

AN:

240162

AF XY:

0.270

show subpopulations

Gnomad AFR exome

AF:

0.121

Gnomad AMR exome

AF:

0.262

Gnomad ASJ exome

AF:

0.304

Gnomad EAS exome

AF:

0.368

Gnomad FIN exome

AF:

0.256

Gnomad NFE exome

AF:

0.262

Gnomad OTH exome

AF:

0.262

GnomAD4 exome

AF:

0.263

AC:

380812

AN:

1450050

Hom.:

51313

Cov.:

AF XY:

0.264

AC XY:

190496

AN XY:

720234

show subpopulations

African (AFR)

AF:

0.120

AC:

3967

AN:

33018

American (AMR)

AF:

0.261

AC:

11118

AN:

42544

Ashkenazi Jewish (ASJ)

AF:

0.298

AC:

7659

AN:

25728

East Asian (EAS)

AF:

0.392

AC:

15508

AN:

39536

South Asian (SAS)

AF:

0.301

AC:

25308

AN:

84120

European-Finnish (FIN)

AF:

0.259

AC:

13810

AN:

53234

Middle Eastern (MID)

AF:

0.299

AC:

1711

AN:

5714

European-Non Finnish (NFE)

AF:

0.259

AC:

286091

AN:

1106238

Other (OTH)

AF:

0.261

AC:

15640

AN:

59918

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

12423

24845

37268

49690

62113

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9684

19368

29052

38736

48420

<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:

0.228

AC:

34719

AN:

152066

Hom.:

4340

Cov.:

AF XY:

0.229

AC XY:

17051

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.128

AC:

5329

AN:

41510

American (AMR)

AF:

0.255

AC:

3899

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.307

AC:

1063

AN:

3466

East Asian (EAS)

AF:

0.365

AC:

1878

AN:

5150

South Asian (SAS)

AF:

0.296

AC:

1428

AN:

4820

European-Finnish (FIN)

AF:

0.263

AC:

2773

AN:

10554

Middle Eastern (MID)

AF:

0.262

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.258

AC:

17504

AN:

67972

Other (OTH)

AF:

0.231

AC:

486

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1350

2700

4051

5401

6751

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

378

756

1134

1512

1890

<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:

0.246

Hom.:

13596

Bravo

AF:

0.221

Asia WGS

AF:

0.335

AC:

1162

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.98

(source)

DANN

Benign

0.58

PhyloP100

0.41

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over