2-99554731-T-C

Position:

• chr2-99554731-T-C

Variant summary

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

The NM_001386135.1(AFF3):​c.3287A>G​(p.Asn1096Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AFF3 NM_001386135.1 missense, splice_region
• Scores: Splicing: ADA: 0.1600
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.55

Genes affected

AFF3 (HGNC:6473): (ALF transcription elongation factor 3) This gene encodes a tissue-restricted nuclear transcriptional activator that is preferentially expressed in lymphoid tissue. Isolation of this protein initially defined a highly conserved LAF4/MLLT2 gene family of nuclear transcription factors that may function in lymphoid development and oncogenesis. In some ALL patients, this gene has been found fused to the gene for MLL. Multiple alternatively spliced transcript variants that encode different proteins have been found for this gene. [provided by RefSeq, Jul 2008]

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=0.23692724).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AFF3	NM_001386135.1	c.3287A>G	p.Asn1096Ser	missense_variant, splice_region_variant	23/25	ENST00000672756.2	NP_001373064.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AFF3	ENST00000672756.2	c.3287A>G	p.Asn1096Ser	missense_variant, splice_region_variant	23/25		NM_001386135.1	ENSP00000500419	A2

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

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 28, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.083	T;T;.;.
Eigen	Benign	-0.088
Eigen_PC	Benign	0.051
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.86	.;D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.24	T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.2	L;L;.;.
MutationTaster	Benign	0.87	D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.2	D;D;D;D
REVEL	Benign	0.17
Sift	Benign	0.16	T;T;T;T
Sift4G	Benign	0.066	T;T;T;T
Polyphen		0.015	B;B;P;.
Vest4		0.32
MutPred		0.73		Gain of disorder (P = 0.0448);Gain of disorder (P = 0.0448);.;.;
MVP		0.35
ClinPred		0.57	D
GERP RS		5.6
Varity_R		0.077
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.16
dbscSNV1_RF	Benign	0.45
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: chr2-100171193;