rs786205680

Variant names:

• chr5-132934293-G-A
• rs786205680
• NM_014423.4:c.772C>T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_014423.4(AFF4):​c.772C>T​(p.Arg258Trp) 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 pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AFF4 NM_014423.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.41

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 14 ACMG points.

• PM1: In a region_of_interest Disordered (size 236) in uniprot entity AFF4_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_014423.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.936
• PP5: Variant 5-132934293-G-A is Pathogenic according to our data. Variant chr5-132934293-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 190331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132934293-G-A is described in Lovd as [Pathogenic]. Variant chr5-132934293-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFF4	NM_014423.4	c.772C>T	p.Arg258Trp	missense_variant	Exon 3 of 21	ENST00000265343.10	NP_055238.1
AFF4	XM_005271963.6	c.772C>T	p.Arg258Trp	missense_variant	Exon 4 of 22		XP_005272020.1
AFF4	XM_006714587.5	c.772C>T	p.Arg258Trp	missense_variant	Exon 3 of 20		XP_006714650.1
AFF4	XM_047417103.1	c.772C>T	p.Arg258Trp	missense_variant	Exon 4 of 21		XP_047273059.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFF4	ENST00000265343.10	c.772C>T	p.Arg258Trp	missense_variant	Exon 3 of 21	1	NM_014423.4	ENSP00000265343.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome Pathogenic:3

Apr 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 28, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine with tryptophan at codon 258 of the AFF4 protein (p.Arg258Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in an individual affected with CHOPS syndrome (PMID: 25730767). ClinVar contains an entry for this variant (Variation ID: 190331). Experimental studies have shown that this missense change leads to increased AFF4 protein levels and higher expression of transcriptional target genes (PMID: 25730767). For these reasons, this variant has been classified as Pathogenic. -

Aug 07, 2018

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Sep 26, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R258W variant in the AFF4 gene has been reported previously as a de novo sequence change in anindividual with CHOPS syndrome who presented with cognitive impairment, coarse features, heart defects,obesity, pulmonary involvement and short stature (Izumi et al., 2015). Functional studies supportedpathogenicity in that R258W results in a significantly reduced proteosomal degradation in anoverexpression model using HEK-293T cells, whereas transcriptional targets MYC gene and JUN genewere upregulated in the variant compared to wild type in this overexpression model. In addition, patient-derived fibroblasts had significantly elevated AFF4 protein levels, and upregulation of MYC expression, butnot that of JUN (Izumi et al., 2015). Furthermore, missense variants in nearby residues (T254A, T254S)have been reported in the Human Gene Mutation Database in association with CHOPS syndrome(Stenson et al., 2014), supporting the functional importance of this region of the protein. The R258Wsubstitution was not observed in approximately 6500 individuals of European and African American ancestryin the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.The R258W variant is a non-conservative amino acid substitution, which is likely to impact secondaryprotein structure as these residues differ in polarity, charge, size and/or other properties. This substitutionoccurs at a position that is conserved across species. In silico analysis predicts this variant is probablydamaging to the protein structure/function. We interpret R258W as a pathogenic variant. -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

AFF4: PM2, PM6, PS4:Moderate, PP3, PS3:Supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Pathogenic	3.2	M;M
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.7	D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.92
MutPred		0.77		Loss of MoRF binding (P = 0.0621);Loss of MoRF binding (P = 0.0621);
MVP		0.80
MPC		1.0
ClinPred		1.0	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.88
gMVP		0.64

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: rs786205680; hg19: chr5-132269985; COSMIC: COSV99534537; COSMIC: COSV99534537;