18-56611069-T-C

Variant names:

• chr18-56611069-T-C
• rs1368378305
• NM_004786.3:c.764A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004786.3(TXNL1):​c.764A>G​(p.Glu255Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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: 5.77

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39574692).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNL1	NM_004786.3	c.764A>G	p.Glu255Gly	missense_variant	Exon 7 of 8	ENST00000217515.11	NP_004777.1
TXNL1	XM_024451289.2	c.764A>G	p.Glu255Gly	missense_variant	Exon 7 of 9		XP_024307057.1
TXNL1	XM_024451290.2	c.764A>G	p.Glu255Gly	missense_variant	Exon 7 of 8		XP_024307058.1
TXNL1	NR_024546.2	n.1021A>G		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.764A>G	p.Glu255Gly	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

Jul 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.764A>G (p.E255G) alteration is located in exon 7 (coding exon 7) of the TXNL1 gene. This alteration results from a A to G substitution at nucleotide position 764, causing the glutamic acid (E) at amino acid position 255 to be replaced by a glycine (G). 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	0.18
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T
Eigen	Benign	0.041
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	.;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.40	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;L
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.4	N;.
REVEL	Benign	0.13
Sift	Benign	0.46	T;.
Sift4G	Benign	0.40	T;T
Polyphen		0.0010	B;B
Vest4		0.62
MutPred		0.51		Gain of sheet (P = 0.0085);Gain of sheet (P = 0.0085);
MVP		0.23
MPC		0.58
ClinPred		0.85	D
GERP RS		5.8
Varity_R		0.19
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1368378305; hg19: chr18-54278300; COSMIC: COSV54179229;