rs55656741

Variant names:

• chr5-31515550-G-A
• rs55656741
• NM_001382508.1:c.962C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-31515550-G-A
• chr5-31515550-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001382508.1(DROSHA):​c.962C>T​(p.Ser321Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.46 in 1,548,624 control chromosomes in the GnomAD database, including 172,082 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.36 (12285 hom., cov: 33)
  • Exomes 𝑓: 0.47 (159797 hom.)
• Consequence: DROSHA NM_001382508.1 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.960
• Publications: 30 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.9096346E-4).
• BP6: Variant 5-31515550-G-A is Benign according to our data. Variant chr5-31515550-G-A is described in ClinVar as Benign. ClinVar VariationId is 3059023.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.493 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.962C>T	p.Ser321Leu	missense	Exon 7 of 36	NP_001369437.1	Q9NRR4-1
	DROSHA	NM_013235.5		c.962C>T	p.Ser321Leu	missense	Exon 6 of 35	NP_037367.3
	DROSHA	NM_001100412.2		c.948-331C>T		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.962C>T	p.Ser321Leu	missense	Exon 7 of 36	ENSP00000339845.3	Q9NRR4-1
	DROSHA	ENST00000511367.6	TSL:1	c.962C>T	p.Ser321Leu	missense	Exon 6 of 35	ENSP00000425979.2	Q9NRR4-1
	DROSHA	ENST00000513349.5	TSL:1	c.948-331C>T		intron	N/A	ENSP00000424161.1	Q9NRR4-4

Frequencies

GnomAD3 genomes AF: 0.362 AC: 54972 AN: 151998 Hom.: 12286 Cov.: 33

Gnomad AFR AF: 0.0935

Gnomad AMI AF: 0.520

Gnomad AMR AF: 0.409

Gnomad ASJ AF: 0.399

Gnomad EAS AF: 0.197

Gnomad SAS AF: 0.477

Gnomad FIN AF: 0.466

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.498

Gnomad OTH AF: 0.384

GnomAD2 exomes AF: 0.432 AC: 66716 AN: 154384 AF XY: 0.439

Gnomad AFR exome AF: 0.0875

Gnomad AMR exome AF: 0.441

Gnomad ASJ exome AF: 0.404

Gnomad EAS exome AF: 0.201

Gnomad FIN exome AF: 0.473

Gnomad NFE exome AF: 0.492

Gnomad OTH exome AF: 0.437

GnomAD4 exome AF: 0.470 AC: 657025 AN: 1396508 Hom.: 159797 Cov.: 34 AF XY: 0.471 AC XY: 324779 AN XY: 688940

African (AFR) AF: 0.0803 AC: 2536 AN: 31562

American (AMR) AF: 0.430 AC: 15340 AN: 35648

Ashkenazi Jewish (ASJ) AF: 0.407 AC: 10233 AN: 25146

East Asian (EAS) AF: 0.190 AC: 6787 AN: 35728

South Asian (SAS) AF: 0.477 AC: 37766 AN: 79094

European-Finnish (FIN) AF: 0.472 AC: 23244 AN: 49252

Middle Eastern (MID) AF: 0.374 AC: 2122 AN: 5668

European-Non Finnish (NFE) AF: 0.496 AC: 533894 AN: 1076508

Other (OTH) AF: 0.434 AC: 25103 AN: 57902

GnomAD4 genome AF: 0.361 AC: 54975 AN: 152116 Hom.: 12285 Cov.: 33 AF XY: 0.363 AC XY: 27009 AN XY: 74346

African (AFR) AF: 0.0933 AC: 3872 AN: 41514

American (AMR) AF: 0.409 AC: 6255 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.399 AC: 1384 AN: 3470

East Asian (EAS) AF: 0.198 AC: 1024 AN: 5180

South Asian (SAS) AF: 0.479 AC: 2310 AN: 4822

European-Finnish (FIN) AF: 0.466 AC: 4924 AN: 10560

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.498 AC: 33823 AN: 67964

Other (OTH) AF: 0.382 AC: 809 AN: 2116

Alfa AF: 0.436 Hom.: 35218

Bravo AF: 0.343

TwinsUK AF: 0.497 AC: 1844

ALSPAC AF: 0.489 AC: 1884

ESP6500AA AF: 0.104 AC: 196

ESP6500EA AF: 0.491 AC: 2054

ExAC AF: 0.392 AC: 10229

Asia WGS AF: 0.303 AC: 1058 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	DROSHA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	18
DANN	Benign	0.82
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.00049	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.96
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.040
Sift	Uncertain	0.017	D
Sift4G	Benign	0.63	T
Polyphen		0.0	B
Vest4		0.17
MPC		0.10
ClinPred		0.0052	T
GERP RS		2.0
Varity_R		0.048
gMVP		0.35
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs55656741; hg19: chr5-31515657; COSMIC: COSV60772644;