1-47225494-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001290403.2(TAL1):c.395C>G(p.Pro132Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000131 in 1,235,450 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 (★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: TAL1 NM_001290403.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.62

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.41808328).
• BS2: High AC in GnomAd at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAL1	NM_001290403.2	c.395C>G	p.Pro132Arg	missense_variant	3/5	ENST00000691006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAL1	ENST00000691006.1	c.395C>G	p.Pro132Arg	missense_variant	3/5		NM_001290403.2	P1
TAL1	ENST00000294339.3	c.395C>G	p.Pro132Arg	missense_variant	2/4	1		P1
TAL1	ENST00000371884.6	c.395C>G	p.Pro132Arg	missense_variant	3/5	1		P1

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152096 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000131 AC: 142 AN: 1083248 Hom.: 0 Cov.: 33 AF XY: 0.000129 AC XY: 66 AN XY: 512210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000120

Gnomad4 ASJ exome AF: 0.000699

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000705

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000108

Gnomad4 OTH exome AF: 0.000320

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152202 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74412

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000140

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

Feb 01, 2023

The c.395C>G (p.P132R) alteration is located in exon 2 (coding exon 1) of the TAL1 gene. This alteration results from a C to G substitution at nucleotide position 395, causing the proline (P) at amino acid position 132 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	Benign	0.23
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.23	T;T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Benign	0.42	T;T
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	0.74	N;N;N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.6	D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.92	P;P
Vest4		0.20
MutPred		0.32		Loss of glycosylation at P132 (P = 0.0095);Loss of glycosylation at P132 (P = 0.0095);
MVP		0.70
MPC		1.1
ClinPred		0.97	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.45
gMVP		0.65

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: rs886951676; hg19: chr1-47691166;