ENST00000376185.5:n.*1671_*1673delTTT

Variant names:

• chr6-31530261-TAAA-T
• rs3219189
• ENST00000376185.5:n.*1671_*1673delTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000376185.5(ATP6V1G2-DDX39B):​n.*1671_*1673delTTT variant causes a non coding transcript exon change. The variant allele was found at a frequency of 0.00000136 in 737,102 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ATP6V1G2-DDX39B ENST00000376185.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.94
• Publications: 0 publications found

Genes affected

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]

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]

MCCD1 (HGNC:20668): (mitochondrial coiled-coil domain 1) Predicted to be located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000376185.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDX39B	NM_004640.7	MANE Select	c.*170_*172delTTT		3_prime_UTR	Exon 11 of 11	NP_004631.1
	DDX39B	NR_037852.2		n.1422_1424delTTT		non_coding_transcript_exon	Exon 9 of 9
	ATP6V1G2-DDX39B	NR_037853.1		n.2260_2262delTTT		non_coding_transcript_exon	Exon 13 of 13

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V1G2-DDX39B	ENST00000376185.5	TSL:2	n.*1671_*1673delTTT		non_coding_transcript_exon	Exon 13 of 13	ENSP00000365356.1
	DDX39B	ENST00000396172.6	TSL:1 MANE Select	c.*170_*172delTTT		3_prime_UTR	Exon 11 of 11	ENSP00000379475.1
	DDX39B	ENST00000458640.5	TSL:1	c.*170_*172delTTT		3_prime_UTR	Exon 11 of 11	ENSP00000416269.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000136 AC: 1 AN: 737102 Hom.: 0 AF XY: 0.00000269 AC XY: 1 AN XY: 371836

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 17194

American (AMR) AF: 0.00 AC: 0 AN: 18226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15222

East Asian (EAS) AF: 0.0000315 AC: 1 AN: 31772

South Asian (SAS) AF: 0.00 AC: 0 AN: 50140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42930

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2496

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 524280

Other (OTH) AF: 0.00 AC: 0 AN: 34842

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.9

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: rs3219189; hg19: chr6-31498038;