6-31539278-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004640.7(DDX39B):c.212-4T>C 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 0.00249 in 1,609,516 control chromosomes in the GnomAD database, including 155 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 0.0033 (33 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (122 hom.)
• Consequence: DDX39B NM_004640.7 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001674
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.86

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 6-31539278-A-G is Benign according to our data. Variant chr6-31539278-A-G is described in ClinVar as [Benign]. Clinvar id is 707911.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00328 (499/152266) while in subpopulation SAS AF= 0.0506 (244/4824). AF 95% confidence interval is 0.0454. There are 33 homozygotes in gnomad4. There are 345 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 501 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DDX39B	NM_004640.7	c.212-4T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000396172.6
ATP6V1G2-DDX39B	NR_037853.1	n.1015-4T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant
DDX39B	NM_080598.6	c.212-4T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
DDX39B	NR_037852.2	n.397+1044T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDX39B	ENST00000396172.6	c.212-4T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004640.7	P1

Frequencies

GnomAD3 genomes AF: 0.00329 AC: 501 AN: 152148 Hom.: 33 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0466

Gnomad SAS AF: 0.0507

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00665 AC: 1634 AN: 245666 Hom.: 49 AF XY: 0.00728 AC XY: 974 AN XY: 133872

Gnomad AFR exome AF: 0.000199

Gnomad AMR exome AF: 0.000233

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0471

Gnomad SAS exome AF: 0.0244

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000545

Gnomad OTH exome AF: 0.00248

GnomAD4 exome AF: 0.00241 AC: 3516 AN: 1457250 Hom.: 122 Cov.: 33 AF XY: 0.00312 AC XY: 2256 AN XY: 724152

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0238

Gnomad4 SAS exome AF: 0.0261

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000370

Gnomad4 OTH exome AF: 0.00434

GnomAD4 genome AF: 0.00328 AC: 499 AN: 152266 Hom.: 33 Cov.: 32 AF XY: 0.00463 AC XY: 345 AN XY: 74460

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0464

Gnomad4 SAS AF: 0.0506

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000212 Hom.: 0

Bravo AF: 0.00175

Asia WGS AF: 0.0220 AC: 77 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

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

Jun 15, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	6.4
Dann	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000017
dbscSNV1_RF	Benign	0.032
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

Publications

LitVar

Other links and lift over

dbSNP: rs148931659; hg19: chr6-31507055;