5-31410816-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001382508.1(DROSHA):c.3597C>T(p.Tyr1199=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,613,926 control chromosomes in the GnomAD database, including 129 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (13 hom., cov: 33)
  • Exomes 𝑓: 0.010 (116 hom.)
• Consequence: DROSHA NM_001382508.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.524

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 5-31410816-G-A is Benign according to our data. Variant chr5-31410816-G-A is described in ClinVar as [Benign]. Clinvar id is 776037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.524 with no splicing effect.
• BS2: High AC in GnomAd at 1187 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DROSHA	NM_001382508.1	c.3597C>T	p.Tyr1199=	synonymous_variant	31/36	ENST00000344624.8
DROSHA	NM_013235.5	c.3597C>T	p.Tyr1199=	synonymous_variant	30/35
DROSHA	NM_001100412.2	c.3486C>T	p.Tyr1162=	synonymous_variant	30/35

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DROSHA	ENST00000344624.8	c.3597C>T	p.Tyr1199=	synonymous_variant	31/36	5	NM_001382508.1	P4
DROSHA	ENST00000511367.6	c.3597C>T	p.Tyr1199=	synonymous_variant	30/35	1		P4
DROSHA	ENST00000513349.5	c.3486C>T	p.Tyr1162=	synonymous_variant	30/35	1		A1
DROSHA	ENST00000511778.5	n.713C>T		non_coding_transcript_exon_variant	3/8	3

Frequencies

GnomAD3 genomes AF: 0.00780 AC: 1187 AN: 152202 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.00215

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00857

Gnomad ASJ AF: 0.0386

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0121

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0100

Gnomad OTH AF: 0.00958

GnomAD3 exomes AF: 0.00849 AC: 2115 AN: 249034 Hom.: 19 AF XY: 0.00813 AC XY: 1098 AN XY: 135090

Gnomad AFR exome AF: 0.00258

Gnomad AMR exome AF: 0.00663

Gnomad ASJ exome AF: 0.0331

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000882

Gnomad FIN exome AF: 0.0106

Gnomad NFE exome AF: 0.0107

Gnomad OTH exome AF: 0.00910

GnomAD4 exome AF: 0.0105 AC: 15328 AN: 1461606 Hom.: 116 Cov.: 30 AF XY: 0.0101 AC XY: 7360 AN XY: 727092

Gnomad4 AFR exome AF: 0.00170

Gnomad4 AMR exome AF: 0.00695

Gnomad4 ASJ exome AF: 0.0322

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00109

Gnomad4 FIN exome AF: 0.0105

Gnomad4 NFE exome AF: 0.0115

Gnomad4 OTH exome AF: 0.0108

GnomAD4 genome AF: 0.00780 AC: 1188 AN: 152320 Hom.: 13 Cov.: 33 AF XY: 0.00764 AC XY: 569 AN XY: 74482

Gnomad4 AFR AF: 0.00214

Gnomad4 AMR AF: 0.00856

Gnomad4 ASJ AF: 0.0386

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0121

Gnomad4 NFE AF: 0.0100

Gnomad4 OTH AF: 0.00948

Alfa AF: 0.0102 Hom.: 5

Bravo AF: 0.00793

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0116

EpiControl AF: 0.0130

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DROSHA-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 09, 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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	0.27
Dann	Benign	0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs61748189; hg19: chr5-31410923;