1-47219895-C-G

Variant names:

• chr1-47219895-C-G
• rs764186281
• NM_001290403.2:c.821G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001290403.2(TAL1):​c.821G>C​(p.Gly274Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G274D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TAL1 NM_001290403.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.63
• Publications: 1 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.112044334).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001290403.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAL1	NM_001290403.2	MANE Select	c.821G>C	p.Gly274Ala	missense	Exon 5 of 5	NP_001277332.1	P17542-1
	TAL1	NM_001287347.2		c.821G>C	p.Gly274Ala	missense	Exon 5 of 5	NP_001274276.1	Q16509
	TAL1	NM_001290404.1		c.821G>C	p.Gly274Ala	missense	Exon 6 of 6	NP_001277333.1	P17542-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAL1	ENST00000691006.1	MANE Select	c.821G>C	p.Gly274Ala	missense	Exon 5 of 5	ENSP00000510655.1	P17542-1
	TAL1	ENST00000294339.3	TSL:1	c.821G>C	p.Gly274Ala	missense	Exon 4 of 4	ENSP00000294339.3	P17542-1
	TAL1	ENST00000371884.6	TSL:1	c.821G>C	p.Gly274Ala	missense	Exon 5 of 5	ENSP00000360951.1	P17542-1

Frequencies

GnomAD3 genomes AF: 0.000126 AC: 18 AN: 143152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000751

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000687

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000240

Gnomad SAS AF: 0.000258

Gnomad FIN AF: 0.000109

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000170

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00390 AC: 1543 AN: 395286 Hom.: 0 Cov.: 0 AF XY: 0.00324 AC XY: 696 AN XY: 215008

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00251 AC: 28 AN: 11152

American (AMR) AF: 0.0000937 AC: 3 AN: 32024

Ashkenazi Jewish (ASJ) AF: 0.000976 AC: 9 AN: 9218

East Asian (EAS) AF: 0.00106 AC: 15 AN: 14100

South Asian (SAS) AF: 0.000692 AC: 41 AN: 59238

European-Finnish (FIN) AF: 0.000174 AC: 5 AN: 28772

Middle Eastern (MID) AF: 0.00337 AC: 4 AN: 1188

European-Non Finnish (NFE) AF: 0.00619 AC: 1379 AN: 222602

Other (OTH) AF: 0.00347 AC: 59 AN: 16992

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000126 AC: 18 AN: 143292 Hom.: 0 Cov.: 32 AF XY: 0.000129 AC XY: 9 AN XY: 69660

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000749 AC: 3 AN: 40062

American (AMR) AF: 0.0000686 AC: 1 AN: 14584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3310

East Asian (EAS) AF: 0.000240 AC: 1 AN: 4160

South Asian (SAS) AF: 0.000257 AC: 1 AN: 3892

European-Finnish (FIN) AF: 0.000109 AC: 1 AN: 9210

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.000170 AC: 11 AN: 64890

Other (OTH) AF: 0.00 AC: 0 AN: 2032

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.56	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.6
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.14
Sift	Benign	0.054	T
Sift4G	Benign	0.16	T
Polyphen		0.0020	B
Vest4		0.14
MutPred		0.24		Gain of relative solvent accessibility (P = 0.1571)
MVP		0.66
MPC		0.73
ClinPred		0.18	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.073
gMVP		0.22
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

dbSNP: rs764186281; hg19: chr1-47685567;