chr1-47219838-C-G

Position:

• chr1-47219838-C-G

Variant summary

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

The NM_001290403.2(TAL1):​c.878G>C​(p.Ser293Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TAL1 NM_001290403.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.51

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]

TAL1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TAL1	NM_001290403.2	c.878G>C	p.Ser293Thr	missense_variant	5/5	ENST00000691006.1	NP_001277332.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TAL1	ENST00000691006.1	c.878G>C	p.Ser293Thr	missense_variant	5/5		NM_001290403.2	ENSP00000510655.1
TAL1	ENST00000294339.3	c.878G>C	p.Ser293Thr	missense_variant	4/4	1		ENSP00000294339.3
TAL1	ENST00000371884.6	c.878G>C	p.Ser293Thr	missense_variant	5/5	1		ENSP00000360951.1
TAL1	ENST00000459729.1	n.646G>C		non_coding_transcript_exon_variant	3/3	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000166 AC: 2

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

Mar 18, 2024

The c.878G>C (p.S293T) alteration is located in exon 4 (coding exon 3) of the TAL1 gene. This alteration results from a G to C substitution at nucleotide position 878, causing the serine (S) at amino acid position 293 to be replaced by a threonine (T). 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	0.71
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.52	.;T
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.7	N;N
REVEL	Uncertain	0.49
Sift	Benign	0.043	D;D
Sift4G	Benign	0.062	T;T
Polyphen		1.0	D;D
Vest4		0.44
MutPred		0.16		Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);
MVP		0.84
MPC		1.6
ClinPred		0.97	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.43

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: rs752840088; hg19: chr1-47685510;