NM_004640.7:c.433-6C>T

Variant names:

• chr6-31536689-G-A
• rs377444138
• NM_004640.7:c.433-6C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_004640.7(DDX39B):​c.433-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000496 in 1,611,746 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0024 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (3 hom.)
• Consequence: DDX39B NM_004640.7 splice_region, intron
• Scores: Splicing: ADA: 0.00005392
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.832
• Publications: 0 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]

SNORD117 (HGNC:32742): (small nucleolar RNA, C/D box 117)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 6-31536689-G-A is Benign according to our data. Variant chr6-31536689-G-A is described in ClinVar as Benign. ClinVar VariationId is 708774.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 363 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004640.7. 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
	DDX39B	NM_004640.7	MANE Select	c.433-6C>T		splice_region intron	N/A	NP_004631.1	Q13838-1
	DDX39B	NM_080598.6		c.433-6C>T		splice_region intron	N/A	NP_542165.1	Q13838-1
	DDX39B	NR_037852.2		n.398-6C>T		splice_region intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDX39B	ENST00000396172.6	TSL:1 MANE Select	c.433-6C>T		splice_region intron	N/A	ENSP00000379475.1	Q13838-1
	DDX39B	ENST00000458640.5	TSL:1	c.433-6C>T		splice_region intron	N/A	ENSP00000416269.1	Q13838-1
	ATP6V1G2-DDX39B	ENST00000376185.5	TSL:2	n.*647-6C>T		splice_region intron	N/A	ENSP00000365356.1	F2Z307

Frequencies

GnomAD3 genomes AF: 0.00238 AC: 361 AN: 151834 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00741

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00250

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000947

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.000798 AC: 196 AN: 245586 AF XY: 0.000605

Gnomad AFR exome AF: 0.00858

Gnomad AMR exome AF: 0.00137

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000471

Gnomad NFE exome AF: 0.000145

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000299 AC: 437 AN: 1459794 Hom.: 3 Cov.: 31 AF XY: 0.000259 AC XY: 188 AN XY: 726258

African (AFR) AF: 0.00479 AC: 160 AN: 33402

American (AMR) AF: 0.00173 AC: 77 AN: 44576

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86186

European-Finnish (FIN) AF: 0.0000961 AC: 5 AN: 52004

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.000135 AC: 150 AN: 1111710

Other (OTH) AF: 0.000514 AC: 31 AN: 60356

GnomAD4 genome AF: 0.00239 AC: 363 AN: 151952 Hom.: 3 Cov.: 32 AF XY: 0.00229 AC XY: 170 AN XY: 74274

African (AFR) AF: 0.00744 AC: 308 AN: 41408

American (AMR) AF: 0.00249 AC: 38 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.0000947 AC: 1 AN: 10562

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67970

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

Alfa AF: 0.00135 Hom.: 0

Bravo AF: 0.00270

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.2
DANN	Benign	0.83
PhyloP100		0.83
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000054
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.010		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: rs377444138; hg19: chr6-31504466;