4-87102147-A-G

Variant names:

• chr4-87102147-A-G
• rs3775214
• NM_001166693.3:c.1284-3481A>G

Variant summary

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

The NM_001166693.3(AFF1):​c.1284-3481A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.341 in 152,114 control chromosomes in the GnomAD database, including 9,513 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 0.34 (9513 hom., cov: 33)
• Consequence: AFF1 NM_001166693.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.13
• Publications: 13 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=-0.6).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.487 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFF1	NM_001166693.3	c.1284-3481A>G		intron_variant	Intron 8 of 20	ENST00000395146.9	NP_001160165.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFF1	ENST00000395146.9	c.1284-3481A>G		intron_variant	Intron 8 of 20	2	NM_001166693.3	ENSP00000378578.4

Frequencies

GnomAD3 genomes AF: 0.341 AC: 51786 AN: 151996 Hom.: 9509 Cov.: 33

Gnomad AFR AF: 0.202

Gnomad AMI AF: 0.305

Gnomad AMR AF: 0.315

Gnomad ASJ AF: 0.255

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.504

Gnomad FIN AF: 0.463

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.399

Gnomad OTH AF: 0.331

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

GnomAD4 genome AF: 0.341 AC: 51816 AN: 152114 Hom.: 9513 Cov.: 33 AF XY: 0.346 AC XY: 25709 AN XY: 74358

African (AFR) AF: 0.202 AC: 8392 AN: 41520

American (AMR) AF: 0.315 AC: 4819 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 887 AN: 3472

East Asian (EAS) AF: 0.431 AC: 2231 AN: 5172

South Asian (SAS) AF: 0.504 AC: 2429 AN: 4820

European-Finnish (FIN) AF: 0.463 AC: 4884 AN: 10542

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.399 AC: 27125 AN: 67978

Other (OTH) AF: 0.327 AC: 690 AN: 2108

Alfa AF: 0.378 Hom.: 14950

Bravo AF: 0.318

Asia WGS AF: 0.412 AC: 1432 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	6.6
DANN	Benign	0.71
PhyloP100		2.1
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: rs3775214; hg19: chr4-88023299;