4-87047152-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_001166693.3(AFF1):​c.617C>T​(p.Ser206Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

AFF1
NM_001166693.3 missense

Scores

13
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.34
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1
In a modified_residue Phosphoserine (size 0) in uniprot entity AFF1_HUMAN
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AFF1NM_001166693.3 linkuse as main transcriptc.617C>T p.Ser206Phe missense_variant 4/21 ENST00000395146.9 NP_001160165.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AFF1ENST00000395146.9 linkuse as main transcriptc.617C>T p.Ser206Phe missense_variant 4/212 NM_001166693.3 ENSP00000378578 A2P51825-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 09, 2024The c.617C>T (p.S206F) 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 617, causing the serine (S) at amino acid position 206 to be replaced by a phenylalanine (F). 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
0.13
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Uncertain
-0.030
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.11
.;T;T;D;.
Eigen
Uncertain
0.22
Eigen_PC
Benign
0.064
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Uncertain
0.91
D;D;D;D;D
M_CAP
Uncertain
0.089
D
MetaRNN
Uncertain
0.48
T;T;T;T;T
MetaSVM
Uncertain
-0.036
T
MutationAssessor
Uncertain
2.9
.;.;.;M;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Benign
0.47
T
PROVEAN
Uncertain
-3.5
D;D;D;D;.
REVEL
Uncertain
0.40
Sift
Benign
0.038
D;D;D;T;.
Sift4G
Uncertain
0.0020
D;D;D;D;D
Polyphen
1.0
.;.;.;D;.
Vest4
0.19
MutPred
0.45
.;.;.;Loss of phosphorylation at S199 (P = 0.007);Loss of phosphorylation at S199 (P = 0.007);
MVP
0.73
MPC
0.35
ClinPred
0.91
D
GERP RS
4.6
Varity_R
0.26
gMVP
0.53

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: chr4-87968304; API