rs236985

Positions:

• chr4-87087630-G-A

Variant summary

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

The NM_001166693.3(AFF1):​c.1105-2354G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.448 in 152,044 control chromosomes in the GnomAD database, including 15,836 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 0.45 (15836 hom., cov: 32)
• Consequence: AFF1 NM_001166693.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.65

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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.567 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AFF1	NM_001166693.3	c.1105-2354G>A		intron_variant		ENST00000395146.9	NP_001160165.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AFF1	ENST00000395146.9	c.1105-2354G>A		intron_variant		2	NM_001166693.3	ENSP00000378578.4

Frequencies

GnomAD3 genomes AF: 0.448 AC: 67989 AN: 151926 Hom.: 15816 Cov.: 32

Gnomad AFR AF: 0.573

Gnomad AMI AF: 0.305

Gnomad AMR AF: 0.351

Gnomad ASJ AF: 0.261

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.506

Gnomad FIN AF: 0.463

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.401

Gnomad OTH AF: 0.404

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.448 AC: 68057 AN: 152044 Hom.: 15836 Cov.: 32 AF XY: 0.450 AC XY: 33422 AN XY: 74304

Gnomad4 AFR AF: 0.573

Gnomad4 AMR AF: 0.351

Gnomad4 ASJ AF: 0.261

Gnomad4 EAS AF: 0.432

Gnomad4 SAS AF: 0.506

Gnomad4 FIN AF: 0.463

Gnomad4 NFE AF: 0.401

Gnomad4 OTH AF: 0.399

Alfa AF: 0.395 Hom.: 17269

Bravo AF: 0.440

Asia WGS AF: 0.430 AC: 1493 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.010
DANN	Benign	0.29

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: rs236985; hg19: chr4-88008782;