chr4-87137185-A-T

Position:

• chr4-87137185-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001166693.3(AFF1):​c.*1484A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 227,866 control chromosomes in the GnomAD database, including 2,959 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.13 (1709 hom., cov: 32)
  • Exomes 𝑓: 0.16 (1250 hom.)
• Consequence: AFF1 NM_001166693.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.130

Genes affected

AFF1 (HGNC:7135): (ALF transcription elongation factor 1) This gene encodes a member of the AF4/ lymphoid nuclear protein related to the Fragile X E syndrome (FRAXE) family of proteins, which have been implicated in human childhood lymphoblastic leukemia, fragile chromosome X intellectual disability, and ataxia. It is the prevalent mixed-lineage leukemia fusion gene associated with spontaneous acute lymphoblastic leukemia. Members of this family have three conserved domains: an N-terminal homology domain, an AF4/ lymphoid nuclear protein domain, and a C-terminal homology domain. The protein functions as a regulator of RNA polymerase II-mediated transcription through elongation and chromatin remodeling functions. Through RNA interference screens, this gene has been shown to promote the expression of CD133, a plasma membrane glycoprotein required for leukemia cell survival. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AFF1	NM_001166693.3	c.*1484A>T		3_prime_UTR_variant	21/21	ENST00000395146.9	NP_001160165.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AFF1	ENST00000395146.9	c.*1484A>T		3_prime_UTR_variant	21/21	2	NM_001166693.3	ENSP00000378578	A2
AFF1	ENST00000307808.10	c.*1484A>T		3_prime_UTR_variant	20/20	1		ENSP00000305689	P4
AFF1	ENST00000544085.6	c.*1484A>T		3_prime_UTR_variant	20/20	5		ENSP00000440843	A2

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19673 AN: 152130 Hom.: 1710 Cov.: 32

Gnomad AFR AF: 0.0392

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.319

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.100

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.184

Gnomad OTH AF: 0.159

GnomAD4 exome AF: 0.161 AC: 12172 AN: 75618 Hom.: 1250 Cov.: 0 AF XY: 0.166 AC XY: 5811 AN XY: 34964

Gnomad4 AFR exome AF: 0.0419

Gnomad4 AMR exome AF: 0.118

Gnomad4 ASJ exome AF: 0.324

Gnomad4 EAS exome AF: 0.000189

Gnomad4 SAS exome AF: 0.0991

Gnomad4 FIN exome AF: 0.147

Gnomad4 NFE exome AF: 0.191

Gnomad4 OTH exome AF: 0.176

GnomAD4 genome AF: 0.129 AC: 19666 AN: 152248 Hom.: 1709 Cov.: 32 AF XY: 0.125 AC XY: 9314 AN XY: 74444

Gnomad4 AFR AF: 0.0391

Gnomad4 AMR AF: 0.135

Gnomad4 ASJ AF: 0.319

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.100

Gnomad4 FIN AF: 0.128

Gnomad4 NFE AF: 0.184

Gnomad4 OTH AF: 0.157

Alfa AF: 0.153 Hom.: 273

Bravo AF: 0.128

Asia WGS AF: 0.0540 AC: 189 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	5.8
DANN	Benign	0.70

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: rs17703261; hg19: chr4-88058337; COSMIC: COSV57120449; COSMIC: COSV57120449;