chr8-53988175-G-T

Position:

• chr8-53988175-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006756.4(TCEA1):​c.405C>A​(p.Ser135Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TCEA1 NM_006756.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.14

Genes affected

TCEA1 (HGNC:11612): (transcription elongation factor A1) Predicted to enable DNA binding activity; translation elongation factor activity; and zinc ion binding activity. Predicted to be involved in positive regulation of transcription by RNA polymerase II. Predicted to act upstream of or within erythrocyte differentiation and positive regulation of transcription, DNA-templated. Located in nucleolus and nucleoplasm. Part of transcription factor TFIID complex. [provided by Alliance of Genome Resources, Apr 2022]

TCEA1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.105673164).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCEA1	NM_006756.4	c.405C>A	p.Ser135Arg	missense_variant	5/10	ENST00000521604.7	NP_006747.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCEA1	ENST00000521604.7	c.405C>A	p.Ser135Arg	missense_variant	5/10	1	NM_006756.4	ENSP00000428426.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460700 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726534

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 08, 2024

The c.405C>A (p.S135R) alteration is located in exon 5 (coding exon 5) of the TCEA1 gene. This alteration results from a C to A substitution at nucleotide position 405, causing the serine (S) at amino acid position 135 to be replaced by an arginine (R). 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	0.57
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	.;T;.;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.21
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	.;N;.;.
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-1.7	N;N;.;.
REVEL	Benign	0.074
Sift	Benign	0.53	T;T;.;.
Sift4G	Benign	0.53	T;T;.;.
Polyphen		0.0050	B;B;.;.
Vest4		0.52
MutPred		0.30		.;Loss of phosphorylation at S135 (P = 0.0099);Loss of phosphorylation at S135 (P = 0.0099);.;
MVP		0.47
MPC		0.11
ClinPred		0.25	T
GERP RS		3.8
Varity_R		0.41
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs940240240; hg19: chr8-54900735;