rs786205233

chr5-132934305-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5

The NM_014423.4(AFF4):c.760A>G(p.Thr254Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T254S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AFF4 NM_014423.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.96

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_014423.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-132934304-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 190330.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, AFF4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894
• PP5: Variant 5-132934305-T-C is Pathogenic according to our data. Variant chr5-132934305-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 190329.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-132934305-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AFF4	NM_014423.4	c.760A>G	p.Thr254Ala	missense_variant	3/21	ENST00000265343.10
AFF4	XM_005271963.6	c.760A>G	p.Thr254Ala	missense_variant	4/22
AFF4	XM_006714587.5	c.760A>G	p.Thr254Ala	missense_variant	3/20
AFF4	XM_047417103.1	c.760A>G	p.Thr254Ala	missense_variant	4/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AFF4	ENST00000265343.10	c.760A>G	p.Thr254Ala	missense_variant	3/21	1	NM_014423.4	P1
AFF4	ENST00000378595.7	c.760A>G	p.Thr254Ala	missense_variant	3/13	1
AFF4	ENST00000465484.1	n.1019A>G		non_coding_transcript_exon_variant	3/5	1
AFF4	ENST00000491831.5	n.1020A>G		non_coding_transcript_exon_variant	3/7	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Pathogenic	3.2	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	D;D
Vest4		0.94
MutPred		0.55		Loss of phosphorylation at T254 (P = 0.0131);Loss of phosphorylation at T254 (P = 0.0131);
MVP		0.84
MPC		1.0
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs786205233; hg19: chr5-132269997;