18-56611057-C-T

Variant names:

• chr18-56611057-C-T
• NM_004786.3:c.776G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004786.3(TXNL1):​c.776G>A​(p.Arg259Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TXNL1 NM_004786.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.21

Genes affected

TXNL1 (HGNC:12436): (thioredoxin like 1) Enables disulfide oxidoreductase activity. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1405246).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNL1	NM_004786.3	c.776G>A	p.Arg259Lys	missense_variant	Exon 7 of 8	ENST00000217515.11	NP_004777.1
TXNL1	XM_024451289.2	c.776G>A	p.Arg259Lys	missense_variant	Exon 7 of 9		XP_024307057.1
TXNL1	XM_024451290.2	c.776G>A	p.Arg259Lys	missense_variant	Exon 7 of 8		XP_024307058.1
TXNL1	NR_024546.2	n.1033G>A		non_coding_transcript_exon_variant	Exon 8 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TXNL1	ENST00000217515.11	c.776G>A	p.Arg259Lys	missense_variant	Exon 7 of 8	1	NM_004786.3	ENSP00000217515.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.776G>A (p.R259K) alteration is located in exon 7 (coding exon 7) of the TXNL1 gene. This alteration results from a G to A substitution at nucleotide position 776, causing the arginine (R) at amino acid position 259 to be replaced by a lysine (K). 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	Benign	0.085
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.069
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.84	.;T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.27	N;N
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.32	N;.
REVEL	Benign	0.082
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.0090	B;B
Vest4		0.22
MutPred		0.60		Gain of sheet (P = 0.0125);Gain of sheet (P = 0.0125);
MVP		0.16
MPC		0.48
ClinPred		0.82	D
GERP RS		4.9
Varity_R		0.24
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-54278288;