5-31486433-A-G

Variant names:

• chr5-31486433-A-G
• rs7735863
• NM_001382508.1:c.1914+58T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001382508.1(DROSHA):​c.1914+58T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.868 in 1,550,712 control chromosomes in the GnomAD database, including 595,867 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 0.74 (45741 hom., cov: 33)
  • Exomes 𝑓: 0.88 (550126 hom.)
• Consequence: DROSHA NM_001382508.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.354
• Publications: 13 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.903 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DROSHA	NM_001382508.1	MANE Select	c.1914+58T>C		intron	N/A	NP_001369437.1	Q9NRR4-1
	DROSHA	NM_013235.5		c.1914+58T>C		intron	N/A	NP_037367.3
	DROSHA	NM_001100412.2		c.1803+58T>C		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.1914+58T>C		intron	N/A	ENSP00000339845.3	Q9NRR4-1
	DROSHA	ENST00000511367.6	TSL:1	c.1914+58T>C		intron	N/A	ENSP00000425979.2	Q9NRR4-1
	DROSHA	ENST00000513349.5	TSL:1	c.1803+58T>C		intron	N/A	ENSP00000424161.1	Q9NRR4-4

Frequencies

GnomAD3 genomes AF: 0.745 AC: 113317 AN: 152006 Hom.: 45739 Cov.: 33

Gnomad AFR AF: 0.416

Gnomad AMI AF: 0.922

Gnomad AMR AF: 0.810

Gnomad ASJ AF: 0.871

Gnomad EAS AF: 0.553

Gnomad SAS AF: 0.904

Gnomad FIN AF: 0.847

Gnomad MID AF: 0.807

Gnomad NFE AF: 0.909

Gnomad OTH AF: 0.770

GnomAD4 exome AF: 0.881 AC: 1232795 AN: 1398588 Hom.: 550126 AF XY: 0.884 AC XY: 617020 AN XY: 698088

African (AFR) AF: 0.396 AC: 12503 AN: 31556

American (AMR) AF: 0.823 AC: 33939 AN: 41246

Ashkenazi Jewish (ASJ) AF: 0.871 AC: 21507 AN: 24704

East Asian (EAS) AF: 0.559 AC: 21904 AN: 39152

South Asian (SAS) AF: 0.907 AC: 73916 AN: 81488

European-Finnish (FIN) AF: 0.852 AC: 44746 AN: 52494

Middle Eastern (MID) AF: 0.844 AC: 4712 AN: 5582

European-Non Finnish (NFE) AF: 0.912 AC: 970499 AN: 1064332

Other (OTH) AF: 0.846 AC: 49069 AN: 58034

GnomAD4 genome AF: 0.745 AC: 113331 AN: 152124 Hom.: 45741 Cov.: 33 AF XY: 0.745 AC XY: 55415 AN XY: 74368

African (AFR) AF: 0.415 AC: 17192 AN: 41434

American (AMR) AF: 0.809 AC: 12377 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.871 AC: 3023 AN: 3470

East Asian (EAS) AF: 0.554 AC: 2858 AN: 5160

South Asian (SAS) AF: 0.904 AC: 4355 AN: 4818

European-Finnish (FIN) AF: 0.847 AC: 8976 AN: 10592

Middle Eastern (MID) AF: 0.803 AC: 236 AN: 294

European-Non Finnish (NFE) AF: 0.909 AC: 61848 AN: 68036

Other (OTH) AF: 0.769 AC: 1625 AN: 2112

Alfa AF: 0.855 Hom.: 50544

Bravo AF: 0.723

Asia WGS AF: 0.718 AC: 2500 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.8
DANN	Benign	0.55
PhyloP100		0.35
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7735863; hg19: chr5-31486540; COSMIC: COSV60772637; COSMIC: COSV60772637;