X-103630112-G-T

Variant names:

• chrX-103630112-G-T
• NM_004780.3:c.196G>T

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.196G>T​(p.Glu66*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: TCEAL1 NM_004780.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.29

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 0.592 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-103630112-G-T is Pathogenic according to our data. Variant chrX-103630112-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 3175047.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.196G>T	p.Glu66*	stop_gained	Exon 3 of 3	ENST00000372625.8	NP_004771.2
TCEAL1	NM_001006639.2	c.196G>T	p.Glu66*	stop_gained	Exon 3 of 3		NP_001006640.1
TCEAL1	NM_001006640.2	c.196G>T	p.Glu66*	stop_gained	Exon 3 of 3		NP_001006641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCEAL1	ENST00000372625.8	c.196G>T	p.Glu66*	stop_gained	Exon 3 of 3	1	NM_004780.3	ENSP00000361708.3
TCEAL1	ENST00000372624.3	c.196G>T	p.Glu66*	stop_gained	Exon 3 of 3	1		ENSP00000361707.3
TCEAL1	ENST00000469820.1	n.661G>T		non_coding_transcript_exon_variant	Exon 2 of 2	1
TCEAL1	ENST00000372626.7	c.196G>T	p.Glu66*	stop_gained	Exon 3 of 3	2		ENSP00000361709.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Oct 27, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.196G>T (p.E66*) alteration, located in exon 3 (coding exon 1) of the TCEAL1 gene, consists of a G to T substitution at nucleotide position 196. This changes the amino acid from a glutamic acid (E) to a stop codon at amino acid position 66. Premature stop codons are typically deleterious in nature; however, because TCEAL1 is a single-exon gene this alteration is not expected to trigger nonsense-mediated mRNA decay. This alteration removes the last 93 amino acids of the protein and the exact functional impact of these amino acids is unknown at this time; however the impacted region is critical for protein function and a significant portion of the protein is affected (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	35
DANN	Uncertain	0.99
FATHMM_MKL	Uncertain	0.81	D
Vest4		0.31
ClinPred		1.0	D
GERP RS		2.8

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-102885040;