rs340638

Variant names:

• chr4-87007052-C-T
• rs340638
• ENST00000307808.10:c.-356C>T

Variant summary

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

The ENST00000307808.10(AFF1):​c.-356C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.743 in 1,179,678 control chromosomes in the GnomAD database, including 333,283 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 0.63 (33374 hom., cov: 35)
  • Exomes 𝑓: 0.76 (299909 hom.)
• Consequence: AFF1 ENST00000307808.10 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.26
• Publications: 6 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=-0.65).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.779 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFF1	NM_001166693.3	c.39-39114C>T		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.39-39114C>T		intron_variant	Intron 2 of 20	2	NM_001166693.3	ENSP00000378578.4

Frequencies

GnomAD3 genomes AF: 0.633 AC: 96329 AN: 152104 Hom.: 33371 Cov.: 35

Gnomad AFR AF: 0.334

Gnomad AMI AF: 0.751

Gnomad AMR AF: 0.674

Gnomad ASJ AF: 0.861

Gnomad EAS AF: 0.536

Gnomad SAS AF: 0.799

Gnomad FIN AF: 0.722

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.773

Gnomad OTH AF: 0.671

GnomAD4 exome AF: 0.760 AC: 780567 AN: 1027456 Hom.: 299909 Cov.: 60 AF XY: 0.762 AC XY: 368360 AN XY: 483648

African (AFR) AF: 0.309 AC: 6600 AN: 21362

American (AMR) AF: 0.696 AC: 5006 AN: 7190

Ashkenazi Jewish (ASJ) AF: 0.864 AC: 10961 AN: 12684

East Asian (EAS) AF: 0.548 AC: 10558 AN: 19258

South Asian (SAS) AF: 0.822 AC: 24150 AN: 29394

European-Finnish (FIN) AF: 0.749 AC: 8268 AN: 11036

Middle Eastern (MID) AF: 0.789 AC: 2065 AN: 2618

European-Non Finnish (NFE) AF: 0.773 AC: 683235 AN: 883704

Other (OTH) AF: 0.739 AC: 29724 AN: 40210

GnomAD4 genome AF: 0.633 AC: 96351 AN: 152222 Hom.: 33374 Cov.: 35 AF XY: 0.634 AC XY: 47169 AN XY: 74428

African (AFR) AF: 0.334 AC: 13859 AN: 41538

American (AMR) AF: 0.674 AC: 10313 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.861 AC: 2989 AN: 3472

East Asian (EAS) AF: 0.536 AC: 2773 AN: 5170

South Asian (SAS) AF: 0.800 AC: 3860 AN: 4824

European-Finnish (FIN) AF: 0.722 AC: 7660 AN: 10604

Middle Eastern (MID) AF: 0.769 AC: 226 AN: 294

European-Non Finnish (NFE) AF: 0.773 AC: 52573 AN: 67998

Other (OTH) AF: 0.668 AC: 1413 AN: 2114

Alfa AF: 0.710 Hom.: 78010

Bravo AF: 0.614

Asia WGS AF: 0.671 AC: 2335 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.028
DANN	Benign	0.80
PhyloP100		-4.3
PromoterAI		0.072	Neutral
Mutation Taster		=299/1	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: rs340638; hg19: chr4-87928204; COSMIC: COSV57122483; COSMIC: COSV57122483;