5-132897044-G-C

Position:

• chr5-132897044-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_014423.4(AFF4):​c.1586C>G​(p.Pro529Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P529L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AFF4 NM_014423.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.32

Genes affected

AFF4 (HGNC:17869): (ALF transcription elongation factor 4) The protein encoded by this gene belongs to the AF4 family of transcription factors involved in leukemia. It is a component of the positive transcription elongation factor b (P-TEFb) complex. A chromosomal translocation involving this gene and MLL gene on chromosome 11 is found in infant acute lymphoblastic leukemia with ins(5;11)(q31;q31q23). [provided by RefSeq, Oct 2011]

AFF4 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), AFF4. . Gene score misZ 2.4744 (greater than the threshold 3.09). Trascript score misZ 3.6377 (greater than threshold 3.09). GenCC has associacion of gene with cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AFF4	NM_014423.4	c.1586C>G	p.Pro529Arg	missense_variant	11/21	ENST00000265343.10	NP_055238.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AFF4	ENST00000265343.10	c.1586C>G	p.Pro529Arg	missense_variant	11/21	1	NM_014423.4	ENSP00000265343.5
AFF4	ENST00000378595.7	c.1586C>G	p.Pro529Arg	missense_variant	11/13	1		ENSP00000367858.3
AFF4	ENST00000478588.5	n.664C>G		non_coding_transcript_exon_variant	5/5	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Benign	-0.38	T
MutationAssessor	Pathogenic	2.9	M;M
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-4.4	D;D
REVEL	Uncertain	0.44
Sift	Benign	0.60	T;T
Sift4G	Benign	0.085	T;T
Polyphen		1.0	D;D
Vest4		0.65
MutPred		0.41		Gain of MoRF binding (P = 0.0049);Gain of MoRF binding (P = 0.0049);
MVP		0.54
MPC		1.1
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.45

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: rs188073736; hg19: chr5-132232736;