5-134887967-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_024715.4(TXNDC15):c.376G>A(p.Val126Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000357 in 1,614,206 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00044 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: TXNDC15 NM_024715.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.265

Genes affected

TXNDC15 (HGNC:20652): (thioredoxin domain containing 15) This gene encodes a member of the thioredoxin superfamily. Members of this family are characterized by a conserved active motif called the thioredoxin fold that catalyzes disulfide bond formation and isomerization. [provided by RefSeq, Apr 2017]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005326718).
• BP6: Variant 5-134887967-G-A is Benign according to our data. Variant chr5-134887967-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1591360.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00044 (67/152320) while in subpopulation EAS AF= 0.00174 (9/5184). AF 95% confidence interval is 0.000972. There are 2 homozygotes in gnomad4. There are 33 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TXNDC15	NM_024715.4	c.376G>A	p.Val126Ile	missense_variant	2/5	ENST00000358387.9
TXNDC15	NM_001350735.2	c.172G>A	p.Val58Ile	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TXNDC15	ENST00000358387.9	c.376G>A	p.Val126Ile	missense_variant	2/5	1	NM_024715.4	P1

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152202 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000521 AC: 131 AN: 251418 Hom.: 1 AF XY: 0.000581 AC XY: 79 AN XY: 135886

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00367

Gnomad EAS exome AF: 0.00125

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000352

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000349 AC: 510 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.000360 AC XY: 262 AN XY: 727242

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.00352

Gnomad4 EAS exome AF: 0.000730

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000263

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152320 Hom.: 2 Cov.: 33 AF XY: 0.000443 AC XY: 33 AN XY: 74490

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000392 Hom.: 1

Bravo AF: 0.000453

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000379 AC: 46

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.376G>A (p.V126I) alteration is located in exon 2 (coding exon 2) of the TXNDC15 gene. This alteration results from a G to A substitution at nucleotide position 376, causing the valine (V) at amino acid position 126 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 06, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	8.5
Dann	Benign	0.76
DEOGEN2	Benign	0.013	T;T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.20	T;T;T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.0053	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.13	N;N;N
REVEL	Benign	0.016
Sift	Benign	0.37	T;T;T
Sift4G	Benign	0.60	T;T;T
Polyphen		0.0020	B;.;.
Vest4		0.036
MVP		0.23
MPC		0.15
ClinPred		0.0038	T
GERP RS		-0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.010
gMVP		0.11

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

Publications

LitVar

Other links and lift over

dbSNP: rs149625993; hg19: chr5-134223657; COSMIC: COSV64379576; COSMIC: COSV64379576;