chr5-31409145-A-C

Variant names:

• chr5-31409145-A-C
• rs2241337
• NM_001382508.1:c.3765T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001382508.1(DROSHA):​c.3765T>G​(p.Asn1255Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N1255N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DROSHA NM_001382508.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.87
• Publications: 18 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.773

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.3765T>G	p.Asn1255Lys	missense	Exon 33 of 36	NP_001369437.1	Q9NRR4-1
	DROSHA	NM_013235.5		c.3765T>G	p.Asn1255Lys	missense	Exon 32 of 35	NP_037367.3
	DROSHA	NM_001100412.2		c.3654T>G	p.Asn1218Lys	missense	Exon 32 of 35	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.3765T>G	p.Asn1255Lys	missense	Exon 33 of 36	ENSP00000339845.3	Q9NRR4-1
	DROSHA	ENST00000511367.6	TSL:1	c.3765T>G	p.Asn1255Lys	missense	Exon 32 of 35	ENSP00000425979.2	Q9NRR4-1
	DROSHA	ENST00000513349.5	TSL:1	c.3654T>G	p.Asn1218Lys	missense	Exon 32 of 35	ENSP00000424161.1	Q9NRR4-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 8948

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.028
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.10
Sift	Benign	0.10	T
Sift4G	Benign	0.087	T
Polyphen		0.15	B
Vest4		0.72
MutPred		0.49		Gain of methylation at N1255 (P = 0.0115)
MVP		0.57
MPC		1.3
ClinPred		0.85	D
GERP RS		4.1
Varity_R		0.51
gMVP		0.78
Mutation Taster		=32/68	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2241337; hg19: chr5-31409252;