rs12651081

Positions:

• chr4-86963614-G-A
• chr4-86963614-G-T

Variant summary

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

The NM_001166693.3(AFF1):​c.38+15043G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.458 in 151,966 control chromosomes in the GnomAD database, including 19,264 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 0.46 (19264 hom., cov: 31)
• Consequence: AFF1 NM_001166693.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.389

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=-0.82).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.608 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AFF1	NM_001166693.3	c.38+15043G>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.38+15043G>A		intron_variant		2	NM_001166693.3	ENSP00000378578	A2

Frequencies

GnomAD3 genomes AF: 0.458 AC: 69591 AN: 151848 Hom.: 19268 Cov.: 31

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.634

Gnomad AMR AF: 0.493

Gnomad ASJ AF: 0.695

Gnomad EAS AF: 0.337

Gnomad SAS AF: 0.624

Gnomad FIN AF: 0.564

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.613

Gnomad OTH AF: 0.503

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

GnomAD4 genome AF: 0.458 AC: 69590 AN: 151966 Hom.: 19264 Cov.: 31 AF XY: 0.459 AC XY: 34090 AN XY: 74260

Gnomad4 AFR AF: 0.133

Gnomad4 AMR AF: 0.493

Gnomad4 ASJ AF: 0.695

Gnomad4 EAS AF: 0.336

Gnomad4 SAS AF: 0.624

Gnomad4 FIN AF: 0.564

Gnomad4 NFE AF: 0.613

Gnomad4 OTH AF: 0.503

Alfa AF: 0.579 Hom.: 34742

Bravo AF: 0.438

Asia WGS AF: 0.497 AC: 1732 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.3
DANN	Benign	0.33

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs12651081; hg19: chr4-87884766;