5-31409008-T-C

Position:

• chr5-31409008-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001382508.1(DROSHA):​c.3854+48A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 1,559,842 control chromosomes in the GnomAD database, including 63,483 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 0.35 (11711 hom., cov: 32)
  • Exomes 𝑓: 0.25 (51772 hom.)
• Consequence: DROSHA NM_001382508.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0580

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.651 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DROSHA	NM_001382508.1	c.3854+48A>G		intron_variant		ENST00000344624.8
DROSHA	NM_001100412.2	c.3743+48A>G		intron_variant
DROSHA	NM_013235.5	c.3854+48A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DROSHA	ENST00000344624.8	c.3854+48A>G		intron_variant		5	NM_001382508.1	P4

Frequencies

GnomAD3 genomes AF: 0.351 AC: 53293 AN: 151860 Hom.: 11678 Cov.: 32

Gnomad AFR AF: 0.589

Gnomad AMI AF: 0.287

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.319

Gnomad EAS AF: 0.669

Gnomad SAS AF: 0.382

Gnomad FIN AF: 0.272

Gnomad MID AF: 0.318

Gnomad NFE AF: 0.201

Gnomad OTH AF: 0.330

GnomAD3 exomes AF: 0.312 AC: 70573 AN: 226424 Hom.: 13428 AF XY: 0.305 AC XY: 37257 AN XY: 122262

Gnomad AFR exome AF: 0.603

Gnomad AMR exome AF: 0.344

Gnomad ASJ exome AF: 0.302

Gnomad EAS exome AF: 0.664

Gnomad SAS exome AF: 0.370

Gnomad FIN exome AF: 0.255

Gnomad NFE exome AF: 0.202

Gnomad OTH exome AF: 0.273

GnomAD4 exome AF: 0.246 AC: 345634 AN: 1407864 Hom.: 51772 Cov.: 22 AF XY: 0.248 AC XY: 173632 AN XY: 701080

Gnomad4 AFR exome AF: 0.612

Gnomad4 AMR exome AF: 0.341

Gnomad4 ASJ exome AF: 0.298

Gnomad4 EAS exome AF: 0.711

Gnomad4 SAS exome AF: 0.370

Gnomad4 FIN exome AF: 0.254

Gnomad4 NFE exome AF: 0.200

Gnomad4 OTH exome AF: 0.286

GnomAD4 genome AF: 0.351 AC: 53378 AN: 151978 Hom.: 11711 Cov.: 32 AF XY: 0.356 AC XY: 26480 AN XY: 74288

Gnomad4 AFR AF: 0.589

Gnomad4 AMR AF: 0.328

Gnomad4 ASJ AF: 0.319

Gnomad4 EAS AF: 0.670

Gnomad4 SAS AF: 0.380

Gnomad4 FIN AF: 0.272

Gnomad4 NFE AF: 0.201

Gnomad4 OTH AF: 0.335

Alfa AF: 0.264 Hom.: 1750

Bravo AF: 0.368

Asia WGS AF: 0.539 AC: 1872 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	6.5
DANN	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs644236; hg19: chr5-31409115;