rs3757

Variant names:

• chr22-20111808-G-A
• rs3757
• ENST00000495826.5:n.4631G>A

Variant summary

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

The ENST00000495826.5(DGCR8):​n.4631G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 204,996 control chromosomes in the GnomAD database, including 5,275 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 0.21 (3545 hom., cov: 31)
  • Exomes 𝑓: 0.22 (1730 hom.)
• Consequence: DGCR8 ENST00000495826.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.262
• Publications: 41 publications found

Genes affected

DGCR8 (HGNC:2847): (DGCR8 microprocessor complex subunit) This gene encodes a subunit of the microprocessor complex which mediates the biogenesis of microRNAs from the primary microRNA transcript. The encoded protein is a double-stranded RNA binding protein that functions as the non-catalytic subunit of the microprocessor complex. This protein is required for binding the double-stranded RNA substrate and facilitates cleavage of the RNA by the ribonuclease III protein, Drosha. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jun 2010]

ENSG00000243762 (HGNC:):

TRMT2A (HGNC:24974): (tRNA methyltransferase 2 homolog A) The protein encoded by this gene is of unknown function. However, it is orthologous to the mouse Trmt2a gene and contains an RNA methyltransferase domain. Expression of this gene varies during the cell cycle, with aberrant expression being a possible biomarker in certain breast cancers. Several transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.25 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DGCR8	NM_022720.7	c.*1700G>A		3_prime_UTR_variant	Exon 14 of 14	ENST00000351989.8	NP_073557.3
TRMT2A	NM_022727.6	c.*755C>T		downstream_gene_variant		ENST00000252136.12	NP_073564.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DGCR8	ENST00000351989.8	c.*1700G>A		3_prime_UTR_variant	Exon 14 of 14	1	NM_022720.7	ENSP00000263209.3
TRMT2A	ENST00000252136.12	c.*755C>T		downstream_gene_variant		1	NM_022727.6	ENSP00000252136.7

Frequencies

GnomAD3 genomes AF: 0.208 AC: 31333 AN: 150656 Hom.: 3545 Cov.: 31

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.255

Gnomad AMR AF: 0.257

Gnomad ASJ AF: 0.300

Gnomad EAS AF: 0.187

Gnomad SAS AF: 0.144

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.233

Gnomad OTH AF: 0.222

GnomAD4 exome AF: 0.223 AC: 12070 AN: 54224 Hom.: 1730 Cov.: 0 AF XY: 0.224 AC XY: 6070 AN XY: 27090

African (AFR) AF: 0.107 AC: 245 AN: 2280

American (AMR) AF: 0.256 AC: 390 AN: 1526

Ashkenazi Jewish (ASJ) AF: 0.324 AC: 647 AN: 1996

East Asian (EAS) AF: 0.219 AC: 1159 AN: 5298

South Asian (SAS) AF: 0.101 AC: 52 AN: 514

European-Finnish (FIN) AF: 0.204 AC: 727 AN: 3570

Middle Eastern (MID) AF: 0.333 AC: 86 AN: 258

European-Non Finnish (NFE) AF: 0.226 AC: 7929 AN: 35096

Other (OTH) AF: 0.227 AC: 835 AN: 3686

GnomAD4 genome AF: 0.208 AC: 31341 AN: 150772 Hom.: 3545 Cov.: 31 AF XY: 0.209 AC XY: 15374 AN XY: 73606

African (AFR) AF: 0.137 AC: 5645 AN: 41086

American (AMR) AF: 0.257 AC: 3870 AN: 15082

Ashkenazi Jewish (ASJ) AF: 0.300 AC: 1039 AN: 3468

East Asian (EAS) AF: 0.188 AC: 946 AN: 5044

South Asian (SAS) AF: 0.144 AC: 683 AN: 4742

European-Finnish (FIN) AF: 0.249 AC: 2569 AN: 10310

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.233 AC: 15812 AN: 67750

Other (OTH) AF: 0.218 AC: 457 AN: 2094

Alfa AF: 0.229 Hom.: 4627

Bravo AF: 0.208

Asia WGS AF: 0.156 AC: 543 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.3
DANN	Benign	0.78
PhyloP100		0.26
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: rs3757; hg19: chr22-20099331;