6-31536689-G-A

Variant summary

Our verdict is Benign. Variant got -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, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00005392
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.832

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:):

ACMG classification

Verdict is Benign. Variant got -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 id is 708774.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 361 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DDX39B	NM_004640.7	c.433-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000396172.6
ATP6V1G2-DDX39B	NR_037853.1	n.1236-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant
DDX39B	NM_080598.6	c.433-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
DDX39B	NR_037852.2	n.398-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDX39B	ENST00000396172.6	c.433-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004640.7	P1

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

GnomAD3 exomes AF: 0.000798 AC: 196 AN: 245586 Hom.: 1 AF XY: 0.000605 AC XY: 81 AN XY: 133952

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 SAS exome AF: 0.0000330

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

Gnomad4 AFR exome AF: 0.00479

Gnomad4 AMR exome AF: 0.00173

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000961

Gnomad4 NFE exome AF: 0.000135

Gnomad4 OTH exome AF: 0.000514

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

Gnomad4 AFR AF: 0.00744

Gnomad4 AMR AF: 0.00249

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000947

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.000475

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

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 09, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	5.2
Dann	Benign	0.83

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

Publications

LitVar

Other links and lift over

dbSNP: rs377444138; hg19: chr6-31504466;