X-103630338-GAAAC-G

Variant names:

• chrX-103630338-GAAAC-G
• NM_004780.3:c.427_430delAAAC

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_004780.3(TCEAL1):​c.427_430delAAAC​(p.Lys143fs) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: TCEAL1 NM_004780.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.02

Genes affected

TCEAL1 (HGNC:11616): (transcription elongation factor A like 1) This gene encodes a member of the transcription elongation factor A (SII)-like (TCEAL) gene family. Members of this family may function as nuclear phosphoproteins that modulate transcription in a promoter context-dependent manner. The encoded protein is similar to transcription elongation factor A/transcription factor SII and contains a zinc finger-like motif as well as a sequence related to the transcription factor SII Pol II-binding region. It may exert its effects via protein-protein interactions with other transcriptional regulators rather than via direct binding of DNA. Multiple family members are located on the X chromosome. Alternative splicing results in multiple transcript variants encoding a single isoform. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.11 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-103630338-GAAAC-G is Pathogenic according to our data. Variant chrX-103630338-GAAAC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3376876.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCEAL1	NM_004780.3	c.427_430delAAAC	p.Lys143fs	frameshift_variant	Exon 3 of 3	ENST00000372625.8	NP_004771.2
TCEAL1	NM_001006639.2	c.427_430delAAAC	p.Lys143fs	frameshift_variant	Exon 3 of 3		NP_001006640.1
TCEAL1	NM_001006640.2	c.427_430delAAAC	p.Lys143fs	frameshift_variant	Exon 3 of 3		NP_001006641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCEAL1	ENST00000372625.8	c.427_430delAAAC	p.Lys143fs	frameshift_variant	Exon 3 of 3	1	NM_004780.3	ENSP00000361708.3
TCEAL1	ENST00000372624.3	c.427_430delAAAC	p.Lys143fs	frameshift_variant	Exon 3 of 3	1		ENSP00000361707.3
TCEAL1	ENST00000372626.7	c.427_430delAAAC	p.Lys143fs	frameshift_variant	Exon 3 of 3	2		ENSP00000361709.3
TCEAL1	ENST00000469820.1	n.*122_*125delAAAC		downstream_gene_variant		1

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental disorder with gait disturbance, dysmorphic facies, and behavioral abnormalities, X-linked Pathogenic:1

Oct 09, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, loss of function has been indicated as a likely disease mechanism (PMID: 36368327). (I) 0110 - This gene is associated with X-linked dominant disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0600 - Variant truncates part of the BEX domain (DECIPHER). (I) 0704 - Another downstream truncating variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Trp149*) has been observed as hemizygous and de novo in an individual with a neurodevelopmental disorder (PMID: 36368327). (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-102885266;