6-7883235-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_030810.5(TXNDC5):c.1208G>A(p.Arg403Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00905 in 1,614,122 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0068 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0093 (69 hom.)
• Consequence: TXNDC5 NM_030810.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.98

Genes affected

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]

BLOC1S5-TXNDC5 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008690864).
• BP6: Variant 6-7883235-C-T is Benign according to our data. Variant chr6-7883235-C-T is described in ClinVar as [Benign]. Clinvar id is 780037.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TXNDC5	NM_030810.5	c.1208G>A	p.Arg403Gln	missense_variant	10/10	ENST00000379757.9
BLOC1S5-TXNDC5	NR_037616.1	n.1367G>A		non_coding_transcript_exon_variant	13/13
TXNDC5	NM_001145549.4	c.884G>A	p.Arg295Gln	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TXNDC5	ENST00000379757.9	c.1208G>A	p.Arg403Gln	missense_variant	10/10	1	NM_030810.5	P1
TXNDC5	ENST00000473453.2	c.884G>A	p.Arg295Gln	missense_variant	10/10	1
TXNDC5	ENST00000460138.5	n.986G>A		non_coding_transcript_exon_variant	4/4	2
TXNDC5	ENST00000475802.1	n.502G>A		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes AF: 0.00678 AC: 1032 AN: 152126 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00661

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00510

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0109

Gnomad OTH AF: 0.00863

GnomAD3 exomes AF: 0.00700 AC: 1760 AN: 251260 Hom.: 11 AF XY: 0.00742 AC XY: 1008 AN XY: 135826

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.00665

Gnomad ASJ exome AF: 0.00685

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00310

Gnomad FIN exome AF: 0.00587

Gnomad NFE exome AF: 0.0104

Gnomad OTH exome AF: 0.00733

GnomAD4 exome AF: 0.00928 AC: 13571 AN: 1461878 Hom.: 69 Cov.: 30 AF XY: 0.00898 AC XY: 6534 AN XY: 727236

Gnomad4 AFR exome AF: 0.00128

Gnomad4 AMR exome AF: 0.00678

Gnomad4 ASJ exome AF: 0.00685

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00322

Gnomad4 FIN exome AF: 0.00505

Gnomad4 NFE exome AF: 0.0107

Gnomad4 OTH exome AF: 0.00901

GnomAD4 genome AF: 0.00678 AC: 1032 AN: 152244 Hom.: 4 Cov.: 32 AF XY: 0.00636 AC XY: 473 AN XY: 74420

Gnomad4 AFR AF: 0.00197

Gnomad4 AMR AF: 0.00660

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.00510

Gnomad4 NFE AF: 0.0109

Gnomad4 OTH AF: 0.00854

Alfa AF: 0.00935 Hom.: 8

Bravo AF: 0.00689

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.0127 AC: 109

ExAC AF: 0.00721 AC: 875

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00965

EpiControl AF: 0.00942

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

May 14, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.40
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.10	T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	D;D
MetaRNN	Benign	0.0087	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.84	L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Benign	0.20
Sift	Benign	0.068	T;D
Sift4G	Benign	0.10	T;T
Polyphen		1.0	D;.
Vest4		0.24
MVP		0.35
MPC		0.59
ClinPred		0.036	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.73
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs111331197; hg19: chr6-7883468; COSMIC: COSV51665537; COSMIC: COSV51665537;