chr18-79973854-T-C

Variant names:

• chr18-79973854-T-C
• rs774646403
• NM_006701.5:c.260A>G

Variant summary

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

The NM_006701.5(TXNL4A):​c.260A>G​(p.Asn87Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000958 in 1,460,864 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: TXNL4A NM_006701.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.83

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 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
TXNL4A	NM_006701.5	c.260A>G	p.Asn87Ser	missense_variant, splice_region_variant	Exon 3 of 3	ENST00000269601.10	NP_006692.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TXNL4A	ENST00000269601.10	c.260A>G	p.Asn87Ser	missense_variant, splice_region_variant	Exon 3 of 3	1	NM_006701.5	ENSP00000269601.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000200 AC: 5 AN: 249670 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 134968

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000355

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1460864 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8 AN XY: 726664

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000117

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.260A>G (p.N87S) alteration is located in exon 3 (coding exon 3) of the TXNL4A gene. This alteration results from a A to G substitution at nucleotide position 260, causing the asparagine (N) at amino acid position 87 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Choanal atresia-hearing loss-cardiac defects-craniofacial dysmorphism syndrome Uncertain:1

Apr 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;T;T;T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;.;.;D
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.71	D;D;D;D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Pathogenic	3.7	H;.;.;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-4.5	D;.;.;.
REVEL	Uncertain	0.46
Sift	Benign	0.042	D;.;.;.
Sift4G	Uncertain	0.041	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.65
MutPred		0.65		Gain of catalytic residue at K88 (P = 0.0236);.;.;.;
MVP		0.76
MPC		2.3
ClinPred		0.89	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.58
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs774646403; hg19: chr18-77733854;