ENST00000439343.2:n.*2443A>G

Variant names:

• chr6-7881698-T-C
• rs1043784
• ENST00000439343.2:n.*2443A>G

Variant summary

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

The ENST00000439343.2(BLOC1S5-TXNDC5):​n.*2443A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 152,026 control chromosomes in the GnomAD database, including 4,871 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 0.21 (4871 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BLOC1S5-TXNDC5 ENST00000439343.2 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.94
• Publications: 23 publications found

Genes affected

BLOC1S5-TXNDC5 (HGNC:42001): (BLOC1S5-TXNDC5 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring MUTED (muted homolog) and TXNDC5 (thioredoxin domain containing 5) genes on chromosome 6. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD) and is unlikely to produce a protein product. [provided by RefSeq, Dec 2010]

BMP6 (HGNC:1073): (bone morphogenetic protein 6) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer. This protein regulates a wide range of biological processes including iron homeostasis, fat and bone development, and ovulation. Differential expression of this gene may be associated with progression of breast and prostate cancer. Mutations in this gene may be associated with iron overload in human patients. [provided by RefSeq, Jul 2016]

TXNDC5 (HGNC:21073): (thioredoxin domain containing 5) This gene encodes a member of the disulfide isomerase (PDI) family of endoplasmic reticulum (ER) proteins that catalyze protein folding and thiol-disulfide interchange reactions. The encoded protein has an N-terminal endoplasmic reticulum (ER)-signal sequence, three catalytically active thioredoxin domains and a C-terminal ER-retention sequence. Its expression is induced by hypoxia and its role may be to protect hypoxic cells from apoptosis. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the neighboring upstream BLOC1S5 gene. [provided by RefSeq, Dec 2016]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.434 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMP6	NM_001718.6	c.*1355T>C		3_prime_UTR_variant	Exon 7 of 7	ENST00000283147.7	NP_001709.1
TXNDC5	NM_030810.5	c.*1446A>G		3_prime_UTR_variant	Exon 10 of 10	ENST00000379757.9	NP_110437.2
BLOC1S5-TXNDC5	NR_037616.1	n.2904A>G		non_coding_transcript_exon_variant	Exon 13 of 13
TXNDC5	NM_001145549.4	c.*1446A>G		3_prime_UTR_variant	Exon 10 of 10		NP_001139021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BLOC1S5-TXNDC5	ENST00000439343.2	n.*2443A>G		non_coding_transcript_exon_variant	Exon 13 of 13	2		ENSP00000454697.1
BMP6	ENST00000283147.7	c.*1355T>C		3_prime_UTR_variant	Exon 7 of 7	1	NM_001718.6	ENSP00000283147.6
TXNDC5	ENST00000379757.9	c.*1446A>G		3_prime_UTR_variant	Exon 10 of 10	1	NM_030810.5	ENSP00000369081.4
BLOC1S5-TXNDC5	ENST00000439343.2	n.*2443A>G		3_prime_UTR_variant	Exon 13 of 13	2		ENSP00000454697.1

Frequencies

GnomAD3 genomes AF: 0.209 AC: 31732 AN: 151908 Hom.: 4850 Cov.: 32

Gnomad AFR AF: 0.439

Gnomad AMI AF: 0.0725

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.0965

Gnomad EAS AF: 0.113

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.173

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.177

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.209 AC: 31803 AN: 152026 Hom.: 4871 Cov.: 32 AF XY: 0.209 AC XY: 15533 AN XY: 74314

African (AFR) AF: 0.439 AC: 18174 AN: 41404

American (AMR) AF: 0.143 AC: 2183 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0965 AC: 335 AN: 3470

East Asian (EAS) AF: 0.113 AC: 583 AN: 5174

South Asian (SAS) AF: 0.113 AC: 543 AN: 4826

European-Finnish (FIN) AF: 0.173 AC: 1825 AN: 10558

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.113 AC: 7665 AN: 67996

Other (OTH) AF: 0.179 AC: 379 AN: 2116

Alfa AF: 0.145 Hom.: 2798

Bravo AF: 0.219

Asia WGS AF: 0.157 AC: 547 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.85
DANN	Benign	0.63
PhyloP100		-1.9
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: rs1043784; hg19: chr6-7881931;