rs340630

Variant names:

• chr4-87037243-G-A
• rs340630
• NM_001166693.3:c.39-8923G>A

Variant summary

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

The NM_001166693.3(AFF1):​c.39-8923G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.423 in 152,000 control chromosomes in the GnomAD database, including 16,327 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 0.42 (16327 hom., cov: 31)
• Consequence: AFF1 NM_001166693.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.235
• Publications: 27 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=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.626 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFF1	NM_001166693.3	c.39-8923G>A		intron_variant	Intron 2 of 20	ENST00000395146.9	NP_001160165.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFF1	ENST00000395146.9	c.39-8923G>A		intron_variant	Intron 2 of 20	2	NM_001166693.3	ENSP00000378578.4

Frequencies

GnomAD3 genomes AF: 0.424 AC: 64360 AN: 151882 Hom.: 16324 Cov.: 31

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.552

Gnomad AMR AF: 0.501

Gnomad ASJ AF: 0.448

Gnomad EAS AF: 0.535

Gnomad SAS AF: 0.645

Gnomad FIN AF: 0.531

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.546

Gnomad OTH AF: 0.442

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

GnomAD4 genome AF: 0.423 AC: 64370 AN: 152000 Hom.: 16327 Cov.: 31 AF XY: 0.429 AC XY: 31846 AN XY: 74294

African (AFR) AF: 0.121 AC: 4999 AN: 41456

American (AMR) AF: 0.501 AC: 7660 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.448 AC: 1555 AN: 3472

East Asian (EAS) AF: 0.534 AC: 2765 AN: 5174

South Asian (SAS) AF: 0.645 AC: 3108 AN: 4818

European-Finnish (FIN) AF: 0.531 AC: 5595 AN: 10528

Middle Eastern (MID) AF: 0.418 AC: 123 AN: 294

European-Non Finnish (NFE) AF: 0.546 AC: 37133 AN: 67966

Other (OTH) AF: 0.442 AC: 929 AN: 2104

Alfa AF: 0.514 Hom.: 71545

Bravo AF: 0.405

Asia WGS AF: 0.576 AC: 2003 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.7
DANN	Benign	0.77
PhyloP100		-0.23
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: rs340630; hg19: chr4-87958395;