2-99565539-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.3067A>G(p.Met1023Val) variant causes a missense 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AFF3 NM_001386135.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.43

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=0.2464813).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AFF3	NM_001386135.1	c.3067A>G	p.Met1023Val	missense_variant	20/25	ENST00000672756.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AFF3	ENST00000672756.2	c.3067A>G	p.Met1023Val	missense_variant	20/25		NM_001386135.1	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2023

AFF3: PM2, PP2, BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	21
Dann	Benign	0.96
DEOGEN2	Benign	0.044	T;T;.;.
Eigen	Benign	-0.0039
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.25	T;T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.9	L;L;.;.
MutationTaster	Benign	0.75	D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.8	N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.071	T;T;T;T
Sift4G	Benign	0.22	T;T;T;D
Polyphen		0.0020	B;B;B;.
Vest4		0.31
MutPred		0.45		Gain of relative solvent accessibility (P = 0.0098);Gain of relative solvent accessibility (P = 0.0098);.;.;
MVP		0.49
ClinPred		0.73	D
GERP RS		5.7
Varity_R		0.55
gMVP		0.49

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

LitVar

Other links and lift over

dbSNP: rs1675878628; hg19: chr2-100182001; COSMIC: COSV57857929;