chr4-87047134-C-T

Position:

• chr4-87047134-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001166693.3(AFF1):​c.599C>T​(p.Ala200Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AFF1 NM_001166693.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.603

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]

AFF1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1526773).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AFF1	NM_001166693.3	c.599C>T	p.Ala200Val	missense_variant	4/21	ENST00000395146.9	NP_001160165.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AFF1	ENST00000395146.9	c.599C>T	p.Ala200Val	missense_variant	4/21	2	NM_001166693.3	ENSP00000378578.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2024

The c.599C>T (p.A200V) alteration is located in exon 4 (coding exon 3) of the AFF1 gene. This alteration results from a C to T substitution at nucleotide position 599, causing the alanine (A) at amino acid position 200 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.060	.;T;T;T;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.82	T;T;T;T;T
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.15	T;T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.5	.;.;.;L;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.6	N;N;N;N;.
REVEL	Benign	0.14
Sift	Benign	0.079	T;T;T;T;.
Sift4G	Benign	0.093	T;T;T;T;T
Polyphen		0.66	.;.;.;P;.
Vest4		0.033
MutPred		0.42		.;.;.;Gain of catalytic residue at A193 (P = 0.0502);Gain of catalytic residue at A193 (P = 0.0502);
MVP		0.52
MPC		0.24
ClinPred		0.38	T
GERP RS		2.7
Varity_R		0.075
gMVP		0.27

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-87968286;