rs762124264

Variant names:

• chr5-31405728-TAAATA-T
• rs762124264
• NM_001382508.1:c.3948-10_3948-6delTATTT

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_001382508.1(DROSHA):​c.3948-10_3948-6delTATTT variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000195 in 1,430,738 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00020 (2 hom.)
• Consequence: DROSHA NM_001382508.1 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 4.85
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 5-31405728-TAAATA-T is Benign according to our data. Variant chr5-31405728-TAAATA-T is described in ClinVar as Likely_benign. ClinVar VariationId is 729434.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 28 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DROSHA	NM_001382508.1	MANE Select	c.3948-10_3948-6delTATTT		splice_region intron	N/A	NP_001369437.1	Q9NRR4-1
	DROSHA	NM_013235.5		c.3948-10_3948-6delTATTT		splice_region intron	N/A	NP_037367.3
	DROSHA	NM_001100412.2		c.3837-10_3837-6delTATTT		splice_region intron	N/A	NP_001093882.1	Q9NRR4-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DROSHA	ENST00000344624.8	TSL:5 MANE Select	c.3948-10_3948-6delTATTT		splice_region intron	N/A	ENSP00000339845.3	Q9NRR4-1
	DROSHA	ENST00000511367.6	TSL:1	c.3948-10_3948-6delTATTT		splice_region intron	N/A	ENSP00000425979.2	Q9NRR4-1
	DROSHA	ENST00000513349.5	TSL:1	c.3837-10_3837-6delTATTT		splice_region intron	N/A	ENSP00000424161.1	Q9NRR4-4

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 27 AN: 147128 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000373

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000201

Gnomad SAS AF: 0.000215

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000149

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000147 AC: 20 AN: 136194 AF XY: 0.000179

Gnomad AFR exome AF: 0.000491

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000206

Gnomad OTH exome AF: 0.000552

GnomAD4 exome AF: 0.000196 AC: 251 AN: 1283538 Hom.: 2 AF XY: 0.000181 AC XY: 115 AN XY: 636572

African (AFR) AF: 0.000506 AC: 14 AN: 27666

American (AMR) AF: 0.000107 AC: 3 AN: 28026

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22930

East Asian (EAS) AF: 0.0000291 AC: 1 AN: 34366

South Asian (SAS) AF: 0.000244 AC: 17 AN: 69722

European-Finnish (FIN) AF: 0.0000208 AC: 1 AN: 48072

Middle Eastern (MID) AF: 0.000760 AC: 4 AN: 5260

European-Non Finnish (NFE) AF: 0.000195 AC: 194 AN: 994170

Other (OTH) AF: 0.000319 AC: 17 AN: 53326

GnomAD4 genome AF: 0.000190 AC: 28 AN: 147200 Hom.: 0 Cov.: 31 AF XY: 0.000154 AC XY: 11 AN XY: 71456

African (AFR) AF: 0.000396 AC: 16 AN: 40356

American (AMR) AF: 0.00 AC: 0 AN: 14586

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3438

East Asian (EAS) AF: 0.000202 AC: 1 AN: 4956

South Asian (SAS) AF: 0.000216 AC: 1 AN: 4638

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9024

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.000149 AC: 10 AN: 66986

Other (OTH) AF: 0.00 AC: 0 AN: 2040

Alfa AF: 0.000214 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	DROSHA-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.8
Mutation Taster		=83/17	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs762124264; hg19: chr5-31405835;