5-31429522-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_001382508.1(DROSHA):c.3169C>T(p.Leu1057=) variant causes a synonymous change. The variant allele was found at a frequency of 0.000968 in 1,611,966 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00097 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00097 (1 hom.)
• Consequence: DROSHA NM_001382508.1 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.28

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 5-31429522-G-A is Benign according to our data. Variant chr5-31429522-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3041551.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 148 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DROSHA	NM_001382508.1	c.3169C>T	p.Leu1057=	synonymous_variant	27/36	ENST00000344624.8
DROSHA	NM_013235.5	c.3169C>T	p.Leu1057=	synonymous_variant	26/35
DROSHA	NM_001100412.2	c.3058C>T	p.Leu1020=	synonymous_variant	26/35

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DROSHA	ENST00000344624.8	c.3169C>T	p.Leu1057=	synonymous_variant	27/36	5	NM_001382508.1	P4

Frequencies

GnomAD3 genomes AF: 0.000973 AC: 148 AN: 152042 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00138

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000950 AC: 236 AN: 248312 Hom.: 0 AF XY: 0.000935 AC XY: 126 AN XY: 134724

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.00172

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00124

Gnomad OTH exome AF: 0.00232

GnomAD4 exome AF: 0.000968 AC: 1413 AN: 1459806 Hom.: 1 Cov.: 30 AF XY: 0.000921 AC XY: 669 AN XY: 726146

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00159

Gnomad4 ASJ exome AF: 0.00199

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00110

Gnomad4 OTH exome AF: 0.000979

GnomAD4 genome AF: 0.000973 AC: 148 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.000833 AC XY: 62 AN XY: 74394

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00249

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00138

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00136 Hom.: 0

Bravo AF: 0.00104

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

DROSHA-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 04, 2021

This variant is classified as likely 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
BayesDel_noAF	Benign	-0.39
Cadd	Benign	9.5
Dann	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs61751195; hg19: chr5-31429629;