Genetic Variant NM_030810.5:c.1116G>A (chr6-7884419-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_030810.5(TXNDC5):c.1116G>A(p.Ala372Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,614,088 control chromosomes in the GnomAD database, including 910 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 0.016 ( 151 hom., cov: 32)

Exomes 𝑓: 0.0094 ( 759 hom. )

Consequence

TXNDC5
NM_030810.5 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.888

Publications

8 publications found

Variant links:

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]

TXNDC5 links:

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]

BLOC1S5-TXNDC5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.55).

BP7

Synonymous conserved (PhyloP=-0.888 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TXNDC5	NM_030810.5 link	c.1116G>A	p.Ala372Ala	synonymous_variant	Exon 9 of 10	ENST00000379757.9	NP_110437.2
TXNDC5	NM_001145549.4 link	c.792G>A	p.Ala264Ala	synonymous_variant	Exon 9 of 10		NP_001139021.1
BLOC1S5-TXNDC5	NR_037616.1 link	n.1275G>A		non_coding_transcript_exon_variant	Exon 12 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
TXNDC5	ENST00000379757.9 link	c.1116G>A	p.Ala372Ala	synonymous_variant	Exon 9 of 10	1	NM_030810.5	ENSP00000369081.4
BLOC1S5-TXNDC5	ENST00000439343.2 link	n.*814G>A		non_coding_transcript_exon_variant	Exon 12 of 13	2		ENSP00000454697.1
BLOC1S5-TXNDC5	ENST00000439343.2 link	n.*814G>A		3_prime_UTR_variant	Exon 12 of 13	2		ENSP00000454697.1

Frequencies

GnomAD3 genomes

AF:

0.0160

AC:

2439

AN:

152106

Hom.:

150

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00280

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.0864

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.144

Gnomad SAS

AF:

0.00932

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00207

Gnomad OTH

AF:

0.0225

GnomAD2 exomes

AF:

0.0312

AC:

7849

AN:

251494

AF XY:

0.0261

show subpopulations

Gnomad AFR exome

AF:

0.00351

Gnomad AMR exome

AF:

0.133

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.149

Gnomad FIN exome

AF:

0.000554

Gnomad NFE exome

AF:

0.00126

Gnomad OTH exome

AF:

0.0249

GnomAD4 exome

AF:

0.00945

AC:

13812

AN:

1461864

Hom.:

759

Cov.:

AF XY:

0.00877

AC XY:

6380

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.00206

AC:

AN:

33480

American (AMR)

AF:

0.129

AC:

5760

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26136

East Asian (EAS)

AF:

0.123

AC:

4889

AN:

39690

South Asian (SAS)

AF:

0.00441

AC:

380

AN:

86258

European-Finnish (FIN)

AF:

0.000449

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00174

AC:

1930

AN:

1111992

Other (OTH)

AF:

0.0124

AC:

746

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

727

1454

2182

2909

3636

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

236

472

708

944

1180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0161

AC:

2449

AN:

152224

Hom.:

151

Cov.:

AF XY:

0.0183

AC XY:

1364

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.00279

AC:

116

AN:

41546

American (AMR)

AF:

0.0868

AC:

1326

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.145

AC:

749

AN:

5174

South Asian (SAS)

AF:

0.00953

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00207

AC:

141

AN:

68002

Other (OTH)

AF:

0.0227

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

105

210

316

421

526

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00827

Hom.:

Bravo

AF:

0.0240

Asia WGS

AF:

0.0580

AC:

201

AN:

3478

EpiCase

AF:

0.00109

EpiControl

AF:

0.00154

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

5.6

(source)

DANN

Benign

0.88

PhyloP100

-0.89

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over