1-47219917-C-T

Position:

• chr1-47219917-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.799G>A​(p.Gly267Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000149 in 1,345,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G267D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: TAL1 NM_001290403.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.35

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24425745).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TAL1	NM_001290403.2	c.799G>A	p.Gly267Ser	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.799G>A	p.Gly267Ser	missense_variant	5/5		NM_001290403.2	ENSP00000510655.1
TAL1	ENST00000294339.3	c.799G>A	p.Gly267Ser	missense_variant	4/4	1		ENSP00000294339.3
TAL1	ENST00000371884.6	c.799G>A	p.Gly267Ser	missense_variant	5/5	1		ENSP00000360951.1
TAL1	ENST00000459729.1	n.567G>A		non_coding_transcript_exon_variant	3/3	1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000149 AC: 2 AN: 1345100 Hom.: 0 Cov.: 62 AF XY: 0.00000152 AC XY: 1 AN XY: 656562

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000190

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

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

Nov 17, 2022

The c.799G>A (p.G267S) alteration is located in exon 4 (coding exon 3) of the TAL1 gene. This alteration results from a G to A substitution at nucleotide position 799, causing the glycine (G) at amino acid position 267 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	0.090
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.093	T;T
Eigen	Benign	-0.077
Eigen_PC	Benign	0.071
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.58	.;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Uncertain	-0.017	T
MutationAssessor	Benign	1.1	L;L
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	0.050	N;N
REVEL	Uncertain	0.33
Sift	Benign	0.21	T;T
Sift4G	Benign	0.65	T;T
Polyphen		0.78	P;P
Vest4		0.28
MutPred		0.29		Gain of glycosylation at G267 (P = 0.0017);Gain of glycosylation at G267 (P = 0.0017);
MVP		0.82
MPC		0.68
ClinPred		0.89	D
GERP RS		5.5
Varity_R		0.072
gMVP		0.29

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: rs1479708434; hg19: chr1-47685589;