rs7764128

Variant names:

• chr6-7881972-G-A
• rs7764128
• ENST00000439343.2:n.*2169C>T

Variant summary

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

The ENST00000439343.2(BLOC1S5-TXNDC5):​n.*2169C>T 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 0.208 in 152,584 control chromosomes in the GnomAD database, including 4,809 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 (4805 hom., cov: 32)
  • Exomes 𝑓: 0.15 (4 hom.)
• Consequence: BLOC1S5-TXNDC5 ENST00000439343.2 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.133
• Publications: 17 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]

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]

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]

BMP6 Gene-Disease associations (from GenCC):

• hemochromatosis type 5

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.43 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNDC5	NM_030810.5	c.*1172C>T		3_prime_UTR_variant	Exon 10 of 10	ENST00000379757.9	NP_110437.2
BLOC1S5-TXNDC5	NR_037616.1	n.2630C>T		non_coding_transcript_exon_variant	Exon 13 of 13
TXNDC5	NM_001145549.4	c.*1172C>T		3_prime_UTR_variant	Exon 10 of 10		NP_001139021.1
BMP6	NM_001718.6	c.*1629G>A		downstream_gene_variant		ENST00000283147.7	NP_001709.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BLOC1S5-TXNDC5	ENST00000439343.2	n.*2169C>T		non_coding_transcript_exon_variant	Exon 13 of 13	2		ENSP00000454697.1
TXNDC5	ENST00000379757.9	c.*1172C>T		3_prime_UTR_variant	Exon 10 of 10	1	NM_030810.5	ENSP00000369081.4
BLOC1S5-TXNDC5	ENST00000439343.2	n.*2169C>T		3_prime_UTR_variant	Exon 13 of 13	2		ENSP00000454697.1
BMP6	ENST00000283147.7	c.*1629G>A		downstream_gene_variant		1	NM_001718.6	ENSP00000283147.6

Frequencies

GnomAD3 genomes AF: 0.208 AC: 31576 AN: 152022 Hom.: 4785 Cov.: 32

Gnomad AFR AF: 0.435

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.0965

Gnomad EAS AF: 0.113

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.177

GnomAD4 exome AF: 0.149 AC: 66 AN: 444 Hom.: 4 Cov.: 0 AF XY: 0.159 AC XY: 43 AN XY: 270

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.146 AC: 62 AN: 426

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.200 AC: 2 AN: 10

Other (OTH) AF: 0.333 AC: 2 AN: 6

GnomAD4 genome AF: 0.208 AC: 31645 AN: 152140 Hom.: 4805 Cov.: 32 AF XY: 0.208 AC XY: 15463 AN XY: 74392

African (AFR) AF: 0.435 AC: 18022 AN: 41438

American (AMR) AF: 0.143 AC: 2180 AN: 15296

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

East Asian (EAS) AF: 0.113 AC: 585 AN: 5186

South Asian (SAS) AF: 0.112 AC: 542 AN: 4830

European-Finnish (FIN) AF: 0.172 AC: 1822 AN: 10598

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.113 AC: 7665 AN: 68004

Other (OTH) AF: 0.179 AC: 377 AN: 2112

Alfa AF: 0.162 Hom.: 669

Bravo AF: 0.218

Asia WGS AF: 0.155 AC: 540 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.3
DANN	Benign	0.70
PhyloP100		-0.13
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs7764128; hg19: chr6-7882205;