chr18-79988352-A-C

Position:

• chr18-79988352-A-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP3 BP4_Strong

The NM_006701.5(TXNL4A):​c.41T>G​(p.Val14Gly) 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: 33)
  • Exomes 𝑓: 0.0000043 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TXNL4A NM_006701.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.16

Genes affected

TXNL4A (HGNC:30551): (thioredoxin like 4A) The protein encoded by this gene is a member of the U5 small ribonucleoprotein particle (snRNP), and is involved in pre-mRNA splicing. This protein contains a thioredoxin-like fold and it is expected to interact with multiple proteins. Protein-protein interactions have been observed with the polyglutamine tract-binding protein 1 (PQBP1). Mutations in both the coding region and promoter region of this gene have been associated with Burn-McKeown syndrome, which is a rare disorder characterized by craniofacial dysmorphisms, cardiac defects, hearing loss, and bilateral choanal atresia. A pseudogene of this gene is found on chromosome 2. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2015]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Eigen, M_CAP, MutationAssessor, PROVEAN, REVEL [when max_spliceai, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.029729337).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TXNL4A	NM_006701.5	c.41T>G	p.Val14Gly	missense_variant	1/3	ENST00000269601.10	NP_006692.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TXNL4A	ENST00000269601.10	c.41T>G	p.Val14Gly	missense_variant	1/3	1	NM_006701.5	ENSP00000269601.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000426 AC: 6 AN: 1409480 Hom.: 0 Cov.: 31 AF XY: 0.00000287 AC XY: 2 AN XY: 697378

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000274

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000102

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.000567 AC: 67

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 21, 2024

The c.41T>G (p.V14G) alteration is located in exon 1 (coding exon 1) of the TXNL4A gene. This alteration results from a T to G substitution at nucleotide position 41, causing the valine (V) at amino acid position 14 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	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;T;.
Eigen	Pathogenic	0.81
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.030	T;T;T
MetaSVM	Uncertain	0.55	D
MutationAssessor	Pathogenic	4.2	H;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.3	D;.;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.35
MVP		0.57
MPC		3.4
ClinPred		0.27	T
GERP RS		4.3
Varity_R		0.96
gMVP		0.99

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: rs756259709; hg19: chr18-77748352;