chr14-52457135-C-T

Variant names:

• chr14-52457135-C-T
• rs754734150
• NM_020784.3:c.1658G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020784.3(TXNDC16):​c.1658G>A​(p.Gly553Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000417 in 1,440,498 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: TXNDC16 NM_020784.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.83

Genes affected

TXNDC16 (HGNC:19965): (thioredoxin domain containing 16) Located in endoplasmic reticulum lumen. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNDC16	NM_020784.3	c.1658G>A	p.Gly553Glu	missense_variant	Exon 17 of 21	ENST00000281741.9	NP_065835.2
TXNDC16	NM_001160047.2	c.1643G>A	p.Gly548Glu	missense_variant	Exon 17 of 21		NP_001153519.1
TXNDC16	XR_007064037.1	n.2312G>A		non_coding_transcript_exon_variant	Exon 19 of 19
TXNDC16	XR_007064038.1	n.2188G>A		non_coding_transcript_exon_variant	Exon 18 of 18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TXNDC16	ENST00000281741.9	c.1658G>A	p.Gly553Glu	missense_variant	Exon 17 of 21	1	NM_020784.3	ENSP00000281741.4
TXNDC16	ENST00000555312.1	n.*176G>A		non_coding_transcript_exon_variant	Exon 4 of 5	5		ENSP00000451619.2
TXNDC16	ENST00000555312.1	n.*176G>A		3_prime_UTR_variant	Exon 4 of 5	5		ENSP00000451619.2
TXNDC16	ENST00000554399.1	n.208-16411G>A		intron_variant	Intron 1 of 2	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000173 AC: 4 AN: 230770 Hom.: 0 AF XY: 0.0000160 AC XY: 2 AN XY: 125034

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000138

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000417 AC: 6 AN: 1440498 Hom.: 0 Cov.: 28 AF XY: 0.00000419 AC XY: 3 AN XY: 716332

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000126

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.05e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 08, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1658G>A (p.G553E) alteration is located in exon 17 (coding exon 15) of the TXNDC16 gene. This alteration results from a G to A substitution at nucleotide position 1658, causing the glycine (G) at amino acid position 553 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.033	T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.7	M
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.27
Sift	Uncertain	0.0090	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.48		Gain of solvent accessibility (P = 0.012);
MVP		0.74
MPC		0.18
ClinPred		0.91	D
GERP RS		5.0
Varity_R		0.40
gMVP		0.69

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: rs754734150; hg19: chr14-52923853;