chr4-87137185-A-T

Variant names:

• chr4-87137185-A-T
• rs17703261
• NM_001166693.3:c.*1484A>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.*1484A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 227,866 control chromosomes in the GnomAD database, including 2,959 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 0.13 (1709 hom., cov: 32)
  • Exomes 𝑓: 0.16 (1250 hom.)
• Consequence: AFF1 NM_001166693.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.130
• Publications: 11 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=-0.5).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.181 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.*1484A>T		3_prime_UTR	Exon 21 of 21	NP_001160165.1	P51825-2
	AFF1	NM_001313959.2		c.*1484A>T		3_prime_UTR	Exon 20 of 20	NP_001300888.1	Q14C88
	AFF1	NM_005935.4		c.*1484A>T		3_prime_UTR	Exon 20 of 20	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.*1484A>T		3_prime_UTR	Exon 21 of 21	ENSP00000378578.4	P51825-2
	AFF1	ENST00000307808.10	TSL:1	c.*1484A>T		3_prime_UTR	Exon 20 of 20	ENSP00000305689.6	P51825-1
	AFF1	ENST00000935002.1		c.*1484A>T		3_prime_UTR	Exon 21 of 21	ENSP00000605061.1

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19673 AN: 152130 Hom.: 1710 Cov.: 32

Gnomad AFR AF: 0.0392

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.319

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.100

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.184

Gnomad OTH AF: 0.159

GnomAD4 exome AF: 0.161 AC: 12172 AN: 75618 Hom.: 1250 Cov.: 0 AF XY: 0.166 AC XY: 5811 AN XY: 34964

African (AFR) AF: 0.0419 AC: 150 AN: 3582

American (AMR) AF: 0.118 AC: 271 AN: 2306

Ashkenazi Jewish (ASJ) AF: 0.324 AC: 1532 AN: 4722

East Asian (EAS) AF: 0.000189 AC: 2 AN: 10586

South Asian (SAS) AF: 0.0991 AC: 63 AN: 636

European-Finnish (FIN) AF: 0.147 AC: 71 AN: 482

Middle Eastern (MID) AF: 0.157 AC: 71 AN: 452

European-Non Finnish (NFE) AF: 0.191 AC: 8900 AN: 46538

Other (OTH) AF: 0.176 AC: 1112 AN: 6314

GnomAD4 genome AF: 0.129 AC: 19666 AN: 152248 Hom.: 1709 Cov.: 32 AF XY: 0.125 AC XY: 9314 AN XY: 74444

African (AFR) AF: 0.0391 AC: 1625 AN: 41552

American (AMR) AF: 0.135 AC: 2065 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.319 AC: 1107 AN: 3468

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5190

South Asian (SAS) AF: 0.100 AC: 484 AN: 4824

European-Finnish (FIN) AF: 0.128 AC: 1352 AN: 10598

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.184 AC: 12492 AN: 67994

Other (OTH) AF: 0.157 AC: 333 AN: 2116

Alfa AF: 0.153 Hom.: 273

Bravo AF: 0.128

Asia WGS AF: 0.0540 AC: 189 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	5.8
DANN	Benign	0.70
PhyloP100		0.13
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: rs17703261; hg19: chr4-88058337; COSMIC: COSV57120449; COSMIC: COSV57120449;