1-47225497-G-A

Variant summary

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

The NM_001290403.2(TAL1):c.392C>T(p.Ala131Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000462 in 1,083,366 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000046 (0 hom.)
• Consequence: TAL1 NM_001290403.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.11

Genes affected

TAL1 (HGNC:11556): (TAL bHLH transcription factor 1, erythroid differentiation factor) Enables several functions, including DNA-binding transcription factor activity; E-box binding activity; and histone deacetylase binding activity. Involved in several processes, including myeloid cell differentiation; positive regulation of cellular component organization; and positive regulation of erythrocyte differentiation. Located in chromatin and nucleoplasm. Part of transcription regulator complex. Implicated in acute lymphoblastic leukemia. [provided by Alliance of Genome Resources, Apr 2022]

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=0.24792436).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAL1	NM_001290403.2	c.392C>T	p.Ala131Val	missense_variant	3/5	ENST00000691006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAL1	ENST00000691006.1	c.392C>T	p.Ala131Val	missense_variant	3/5		NM_001290403.2	P1
TAL1	ENST00000294339.3	c.392C>T	p.Ala131Val	missense_variant	2/4	1		P1
TAL1	ENST00000371884.6	c.392C>T	p.Ala131Val	missense_variant	3/5	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000462 AC: 5 AN: 1083366 Hom.: 0 Cov.: 32 AF XY: 0.00000781 AC XY: 4 AN XY: 512286

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000120

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000471

Gnomad4 NFE exome AF: 0.00000217

Gnomad4 OTH exome AF: 0.0000228

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000416

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

Oct 26, 2021

The c.392C>T (p.A131V) alteration is located in exon 2 (coding exon 1) of the TAL1 gene. This alteration results from a C to T substitution at nucleotide position 392, causing the alanine (A) at amino acid position 131 to be replaced by a valine (V). 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	Benign	0.10
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	17
Dann	Uncertain	1.0
DEOGEN2	Benign	0.13	T;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.80	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.25	T;T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.28
Sift	Uncertain	0.016	D;D
Sift4G	Benign	0.18	T;T
Polyphen		0.041	B;B
Vest4		0.13
MutPred		0.20		Loss of glycosylation at P129 (P = 0.0644);Loss of glycosylation at P129 (P = 0.0644);
MVP		0.71
MPC		0.68
ClinPred		0.18	T
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.2
Varity_R		0.059
gMVP		0.19

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

LitVar

Other links and lift over

dbSNP: rs1463781378; hg19: chr1-47691169;