2-99578406-G-C

Variant summary

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

The NM_001386135.1(AFF3):c.2839C>G(p.Arg947Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/23 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: 4.67

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AFF3	NM_001386135.1	c.2839C>G	p.Arg947Gly	missense_variant	18/25	ENST00000672756.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AFF3	ENST00000672756.2	c.2839C>G	p.Arg947Gly	missense_variant	18/25		NM_001386135.1	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2021

The c.2914C>G (p.R972G) alteration is located in exon 17 (coding exon 16) of the AFF3 gene. This alteration results from a C to G substitution at nucleotide position 2914, causing the arginine (R) at amino acid position 972 to be replaced by a glycine (G). 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	0.099
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.024	T;T;.
Eigen	Benign	0.064
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.73	N;N;.
MutationTaster	Benign	0.57	D;D;D;D
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Benign	0.068
Sift	Benign	0.036	D;D;D
Sift4G	Benign	0.37	T;T;T
Polyphen		0.32	B;B;P
Vest4		0.46
MutPred		0.35		Loss of MoRF binding (P = 0.0378);Loss of MoRF binding (P = 0.0378);.;
MVP		0.15
ClinPred		0.74	D
GERP RS		4.4
Varity_R		0.19
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.22		Position offset: 45

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs756186388; hg19: chr2-100194868;