1-47225549-C-T

Variant summary

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

The NM_001290403.2(TAL1):c.340G>A(p.Gly114Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000892 in 1,120,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.9e-7 (0 hom.)
• Consequence: TAL1 NM_001290403.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.49

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=0.1496611).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAL1	NM_001290403.2	c.340G>A	p.Gly114Ser	missense_variant	3/5	ENST00000691006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAL1	ENST00000691006.1	c.340G>A	p.Gly114Ser	missense_variant	3/5		NM_001290403.2	P1
TAL1	ENST00000294339.3	c.340G>A	p.Gly114Ser	missense_variant	2/4	1		P1
TAL1	ENST00000371884.6	c.340G>A	p.Gly114Ser	missense_variant	3/5	1		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.92e-7 AC: 1 AN: 1120826 Hom.: 0 Cov.: 33 AF XY: 0.00000187 AC XY: 1 AN XY: 535428

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000377

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

May 03, 2023

The c.340G>A (p.G114S) alteration is located in exon 2 (coding exon 1) of the TAL1 gene. This alteration results from a G to A substitution at nucleotide position 340, causing the glycine (G) at amino acid position 114 to be replaced by a serine (S). 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	0.087
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	14
Dann	Benign	0.92
DEOGEN2	Benign	0.051	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.70	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	0.46	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.53	N;N
REVEL	Uncertain	0.29
Sift	Benign	0.46	T;T
Sift4G	Benign	0.77	T;T
Polyphen		0.0010	B;B
Vest4		0.096
MutPred		0.20		Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);
MVP		0.57
MPC		0.67
ClinPred		0.053	T
GERP RS		-0.56
Varity_R		0.039
gMVP		0.15

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: rs893544841; hg19: chr1-47691221;