chr6-31530960-G-A

Variant names:

• chr6-31530960-G-A
• rs2516478
• NM_004640.7:c.1123-34C>T

Variant summary

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

The NM_004640.7(DDX39B):​c.1123-34C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.169 in 1,613,492 control chromosomes in the GnomAD database, including 23,752 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 0.16 (2114 hom., cov: 31)
  • Exomes 𝑓: 0.17 (21638 hom.)
• Consequence: DDX39B NM_004640.7 intron
• Scores: Splicing: ADA: 0.00006553
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.30
• Publications: 20 publications found

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

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

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). 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=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.248 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDX39B	NM_004640.7	c.1123-34C>T		intron_variant	Intron 9 of 10	ENST00000396172.6	NP_004631.1
DDX39B	NM_080598.6	c.1123-34C>T		intron_variant	Intron 9 of 10		NP_542165.1
DDX39B	NR_037852.2	n.1088-34C>T		intron_variant	Intron 7 of 8
ATP6V1G2-DDX39B	NR_037853.1	n.1926-34C>T		intron_variant	Intron 11 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDX39B	ENST00000396172.6	c.1123-34C>T		intron_variant	Intron 9 of 10	1	NM_004640.7	ENSP00000379475.1
ATP6V1G2-DDX39B	ENST00000376185.5	n.*1337-34C>T		intron_variant	Intron 11 of 12	2		ENSP00000365356.1

Frequencies

GnomAD3 genomes AF: 0.164 AC: 24901 AN: 151968 Hom.: 2115 Cov.: 31

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.0582

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.194

Gnomad EAS AF: 0.163

Gnomad SAS AF: 0.261

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.184

GnomAD2 exomes AF: 0.179 AC: 44870 AN: 250890 AF XY: 0.186

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.130

Gnomad ASJ exome AF: 0.200

Gnomad EAS exome AF: 0.164

Gnomad FIN exome AF: 0.189

Gnomad NFE exome AF: 0.177

Gnomad OTH exome AF: 0.179

GnomAD4 exome AF: 0.169 AC: 247104 AN: 1461406 Hom.: 21638 Cov.: 38 AF XY: 0.173 AC XY: 125701 AN XY: 726900

African (AFR) AF: 0.145 AC: 4869 AN: 33474

American (AMR) AF: 0.137 AC: 6107 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 5165 AN: 26128

East Asian (EAS) AF: 0.157 AC: 6233 AN: 39682

South Asian (SAS) AF: 0.260 AC: 22390 AN: 86250

European-Finnish (FIN) AF: 0.184 AC: 9820 AN: 53396

Middle Eastern (MID) AF: 0.201 AC: 1162 AN: 5768

European-Non Finnish (NFE) AF: 0.163 AC: 180704 AN: 1111632

Other (OTH) AF: 0.176 AC: 10654 AN: 60366

GnomAD4 genome AF: 0.164 AC: 24918 AN: 152086 Hom.: 2114 Cov.: 31 AF XY: 0.165 AC XY: 12243 AN XY: 74342

African (AFR) AF: 0.143 AC: 5935 AN: 41492

American (AMR) AF: 0.153 AC: 2338 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 674 AN: 3468

East Asian (EAS) AF: 0.163 AC: 843 AN: 5168

South Asian (SAS) AF: 0.260 AC: 1253 AN: 4814

European-Finnish (FIN) AF: 0.179 AC: 1895 AN: 10566

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.169 AC: 11469 AN: 67988

Other (OTH) AF: 0.184 AC: 388 AN: 2104

Alfa AF: 0.164 Hom.: 3033

Bravo AF: 0.162

Asia WGS AF: 0.237 AC: 823 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.41
DANN	Benign	0.53
PhyloP100		-2.3
BranchPoint Hunter		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000066
dbscSNV1_RF	Benign	0.0080
SpliceAI score (max)		0.10		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: rs2516478; hg19: chr6-31498737; COSMIC: COSV66020876; COSMIC: COSV66020876;