6-31535921-T-C

Variant names:

• chr6-31535921-T-C
• rs929138
• NM_004640.7:c.617-436A>G

Variant summary

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

The NM_004640.7(DDX39B):​c.617-436A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 152,198 control chromosomes in the GnomAD database, including 3,868 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 0.22 (3868 hom., cov: 31)
• Consequence: DDX39B NM_004640.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.24
• Publications: 12 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: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.301 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDX39B	NM_004640.7	c.617-436A>G		intron_variant	Intron 5 of 10	ENST00000396172.6	NP_004631.1
DDX39B	NM_080598.6	c.617-436A>G		intron_variant	Intron 5 of 10		NP_542165.1
DDX39B	NR_037852.2	n.582-436A>G		intron_variant	Intron 3 of 8
ATP6V1G2-DDX39B	NR_037853.1	n.1420-436A>G		intron_variant	Intron 7 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDX39B	ENST00000396172.6	c.617-436A>G		intron_variant	Intron 5 of 10	1	NM_004640.7	ENSP00000379475.1
ATP6V1G2-DDX39B	ENST00000376185.5	n.*831-436A>G		intron_variant	Intron 7 of 12	2		ENSP00000365356.1

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32738 AN: 152080 Hom.: 3869 Cov.: 31

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.308

Gnomad ASJ AF: 0.402

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.211

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.246

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.215 AC: 32773 AN: 152198 Hom.: 3868 Cov.: 31 AF XY: 0.213 AC XY: 15849 AN XY: 74406

African (AFR) AF: 0.175 AC: 7279 AN: 41512

American (AMR) AF: 0.308 AC: 4711 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.402 AC: 1394 AN: 3470

East Asian (EAS) AF: 0.184 AC: 953 AN: 5184

South Asian (SAS) AF: 0.210 AC: 1014 AN: 4826

European-Finnish (FIN) AF: 0.103 AC: 1087 AN: 10600

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.228 AC: 15493 AN: 68018

Other (OTH) AF: 0.249 AC: 525 AN: 2112

Alfa AF: 0.220 Hom.: 7243

Bravo AF: 0.231

Asia WGS AF: 0.187 AC: 649 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.013
DANN	Benign	0.52
PhyloP100		-3.2
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: rs929138; hg19: chr6-31503698; COSMIC: COSV63331809; COSMIC: COSV63331809;