4-87109109-G-T

Variant names:

• chr4-87109109-G-T
• rs442177
• NM_001166693.3:c.1533+794G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001166693.3(AFF1):​c.1533+794G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.564 in 151,982 control chromosomes in the GnomAD database, including 24,521 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 0.56 (24521 hom., cov: 32)
• Consequence: AFF1 NM_001166693.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.644
• Publications: 103 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.636 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001166693.3. 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
	AFF1	NM_001166693.3	MANE Select	c.1533+794G>T		intron	N/A	NP_001160165.1	P51825-2
	AFF1	NM_001313959.2		c.1512+794G>T		intron	N/A	NP_001300888.1	Q14C88
	AFF1	NM_005935.4		c.1512+794G>T		intron	N/A	NP_005926.1	P51825-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFF1	ENST00000395146.9	TSL:2 MANE Select	c.1533+794G>T		intron	N/A	ENSP00000378578.4	P51825-2
	AFF1	ENST00000307808.10	TSL:1	c.1512+794G>T		intron	N/A	ENSP00000305689.6	P51825-1
	AFF1	ENST00000935002.1		c.1533+794G>T		intron	N/A	ENSP00000605061.1

Frequencies

GnomAD3 genomes AF: 0.564 AC: 85670 AN: 151862 Hom.: 24498 Cov.: 32

Gnomad AFR AF: 0.489

Gnomad AMI AF: 0.697

Gnomad AMR AF: 0.647

Gnomad ASJ AF: 0.738

Gnomad EAS AF: 0.573

Gnomad SAS AF: 0.492

Gnomad FIN AF: 0.526

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.589

Gnomad OTH AF: 0.599

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

GnomAD4 genome AF: 0.564 AC: 85741 AN: 151982 Hom.: 24521 Cov.: 32 AF XY: 0.561 AC XY: 41700 AN XY: 74280

African (AFR) AF: 0.489 AC: 20263 AN: 41424

American (AMR) AF: 0.647 AC: 9881 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.738 AC: 2558 AN: 3466

East Asian (EAS) AF: 0.572 AC: 2958 AN: 5172

South Asian (SAS) AF: 0.492 AC: 2361 AN: 4798

European-Finnish (FIN) AF: 0.526 AC: 5553 AN: 10560

Middle Eastern (MID) AF: 0.677 AC: 199 AN: 294

European-Non Finnish (NFE) AF: 0.589 AC: 40062 AN: 67978

Other (OTH) AF: 0.603 AC: 1272 AN: 2110

Alfa AF: 0.583 Hom.: 78452

Bravo AF: 0.575

Asia WGS AF: 0.568 AC: 1978 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.5
DANN	Benign	0.61
PhyloP100		-0.64
Mutation Taster		=100/0	polymorphism (auto)

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: rs442177; hg19: chr4-88030261;