dbSNP rs1471586847: TCEAL4:p.Arg49AlafsTer9 (chrX-103577173-A-AG) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PVS1BS2

The NM_001300901.2(TCEAL4):c.144dupG(p.Arg49AlafsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000232 in 1,165,552 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000025 ( 0 hom. 13 hem. )

Consequence

TCEAL4
NM_001300901.2 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: -1.45

Variant links:

Genes affected

TCEAL4 (HGNC:26121): (transcription elongation factor A like 4) This gene encodes a member of the transcription elongation factor A (SII)-like (TCEAL) gene family. This family is comprised of nuclear phosphoproteins that modulate transcription in a promoter context-dependent manner. Multiple family members are located on the X chromosome. Alternatively splicing results in multiple transcript variants. There is a pseudogene for this gene on chromosome 13. [provided by RefSeq, Apr 2015]

TCEAL4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

BS2

High Hemizygotes in GnomAdExome4 at 13 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCEAL4	NM_001300901.2 link	c.144dupG	p.Arg49AlafsTer9	frameshift_variant	Exon 2 of 5		NP_001287830.1	Q96EI5-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCEAL4	ENST00000372629.4 link	c.144dupG	p.Arg49AlafsTer9	frameshift_variant	Exon 2 of 5	1		ENSP00000361712.4		Q96EI5-2

Frequencies

GnomAD3 genomes

AF:

0.00000892

AC:

AN:

112101

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34263

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000182

AC:

AN:

109856

Hom.:

AF XY:

0.00

AC XY:

AN XY:

40124

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000713

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000308

GnomAD4 exome

AF:

0.0000247

AC:

AN:

1053451

Hom.:

Cov.:

AF XY:

0.0000377

AC XY:

AN XY:

344695

show subpopulations

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:

0.000140

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.0000675

GnomAD4 genome

AF:

0.00000892

AC:

AN:

112101

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34263

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Spinocerebellar ataxia 7

Uncertain:1

Feb 02, 2024

Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

The NM_001300901.2: c.144dup (p.Arg49AlafsX9) is a novel de novo frameshift variant in TCEAL4, predicted to result in a truncated or absent protein product. This variant was identified in proband 14, who presented with epilepsy and neurodevelopmental disorders (NDDs) (MIM# 620114), a phenotype consistent with TCEAL4-related conditions (PP1). Sanger sequencing validated the de novo status of the variant within the affected family. The variant was classified as likely pathogenic by multiple in silico prediction tools, including Varsome, Franklin, and ClinVar, in accordance with ACMG criteria (PMID:25741868). Additionally, the variant has been previously reported in the literature as a causative variant for epilepsy-associated NDDs. In summary, this variant meets the criteria to be classified as likely pathogenic for epilepsy-associated NDDs, based on the ACMG/AMP criteria applied: PM2, PP1. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over