rs2516393

Variant names:

• chr6-31538967-A-C
• rs2516393
• NM_004640.7:c.340-112T>G

Your query was ambiguous. Multiple possible variants found:

• chr6-31538967-A-C
• chr6-31538967-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004640.7(DDX39B):​c.340-112T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.829 in 1,471,090 control chromosomes in the GnomAD database, including 506,955 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. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.85 (54741 hom., cov: 32)
  • Exomes 𝑓: 0.83 (452214 hom.)
• Consequence: DDX39B NM_004640.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.115

Genes affected

DDX39B (HGNC:13917): (DExD-box helicase 39B) This gene encodes a member of the DEAD box family of RNA-dependent ATPases that mediate ATP hydrolysis during pre-mRNA splicing. The encoded protein is an essential splicing factor required for association of U2 small nuclear ribonucleoprotein with pre-mRNA, and it also plays an important role in mRNA export from the nucleus to the cytoplasm. This gene belongs to a cluster of genes localized in the vicinity of the genes encoding tumor necrosis factor alpha and tumor necrosis factor beta. These genes are all within the human major histocompatibility complex class III region. Mutations in this gene may be associated with rheumatoid arthritis. Alternative splicing results in multiple transcript variants. Related pseudogenes have been identified on both chromosomes 6 and 11. Read-through transcription also occurs between this gene and the upstream ATP6V1G2 (ATPase, H+ transporting, lysosomal 13kDa, V1 subunit G2) gene. [provided by RefSeq, Feb 2011]

ATP6V1G2-DDX39B (HGNC:41999): (ATP6V1G2-DDX39B readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring ATP6V1G2 (ATPase, H+ transporting, lysosomal 13kDa, V1 subunit G2) and DDX39B (DEAD box polypeptide 39B) genes located in the major histocompatibility complex class III region of chromosome 6. The read-through transcript and is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 4 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.904 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDX39B	NM_004640.7	c.340-112T>G		intron_variant	Intron 3 of 10	ENST00000396172.6	NP_004631.1
DDX39B	NM_080598.6	c.340-112T>G		intron_variant	Intron 3 of 10		NP_542165.1
DDX39B	NR_037852.2	n.397+1355T>G		intron_variant	Intron 2 of 8
ATP6V1G2-DDX39B	NR_037853.1	n.1143-112T>G		intron_variant	Intron 5 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDX39B	ENST00000396172.6	c.340-112T>G		intron_variant	Intron 3 of 10	1	NM_004640.7	ENSP00000379475.1
ATP6V1G2-DDX39B	ENST00000376185.5	n.*554-112T>G		intron_variant	Intron 5 of 12	2		ENSP00000365356.1

Frequencies

GnomAD3 genomes AF: 0.847 AC: 128820 AN: 152032 Hom.: 54684 Cov.: 32

Gnomad AFR AF: 0.876

Gnomad AMI AF: 0.826

Gnomad AMR AF: 0.868

Gnomad ASJ AF: 0.940

Gnomad EAS AF: 0.925

Gnomad SAS AF: 0.923

Gnomad FIN AF: 0.824

Gnomad MID AF: 0.908

Gnomad NFE AF: 0.813

Gnomad OTH AF: 0.860

GnomAD3 exomes AF: 0.856 AC: 212467 AN: 248342 Hom.: 91288 AF XY: 0.861 AC XY: 115894 AN XY: 134646

Gnomad AFR exome AF: 0.873

Gnomad AMR exome AF: 0.857

Gnomad ASJ exome AF: 0.944

Gnomad EAS exome AF: 0.931

Gnomad SAS exome AF: 0.925

Gnomad FIN exome AF: 0.816

Gnomad NFE exome AF: 0.821

Gnomad OTH exome AF: 0.854

GnomAD4 exome AF: 0.826 AC: 1090098 AN: 1318940 Hom.: 452214 Cov.: 21 AF XY: 0.831 AC XY: 551262 AN XY: 663536

Gnomad4 AFR exome AF: 0.882

Gnomad4 AMR exome AF: 0.864

Gnomad4 ASJ exome AF: 0.940

Gnomad4 EAS exome AF: 0.921

Gnomad4 SAS exome AF: 0.926

Gnomad4 FIN exome AF: 0.816

Gnomad4 NFE exome AF: 0.808

Gnomad4 OTH exome AF: 0.835

GnomAD4 genome AF: 0.847 AC: 128935 AN: 152150 Hom.: 54741 Cov.: 32 AF XY: 0.852 AC XY: 63325 AN XY: 74360

Gnomad4 AFR AF: 0.876

Gnomad4 AMR AF: 0.868

Gnomad4 ASJ AF: 0.940

Gnomad4 EAS AF: 0.926

Gnomad4 SAS AF: 0.923

Gnomad4 FIN AF: 0.824

Gnomad4 NFE AF: 0.813

Gnomad4 OTH AF: 0.861

Alfa AF: 0.830 Hom.: 54425

Bravo AF: 0.851

Asia WGS AF: 0.866 AC: 3012 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	13
DANN	Benign	0.59
BranchPoint Hunter		4.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2516393; hg19: chr6-31506744;