rs138116584

Variant names:

• chr5-132892356-G-A
• rs138116584
• NM_014423.4:c.2445C>T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_014423.4(AFF4):​c.2445C>T​(p.Pro815Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000255 in 1,613,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: AFF4 NM_014423.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.00600

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 Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 5-132892356-G-A is Benign according to our data. Variant chr5-132892356-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 434101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.006 with no splicing effect.
• BS2: High AC in GnomAd4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFF4	NM_014423.4	c.2445C>T	p.Pro815Pro	synonymous_variant	Exon 13 of 21	ENST00000265343.10	NP_055238.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFF4	ENST00000265343.10	c.2445C>T	p.Pro815Pro	synonymous_variant	Exon 13 of 21	1	NM_014423.4	ENSP00000265343.5
AFF4	ENST00000378595.7	c.2445C>T	p.Pro815Pro	synonymous_variant	Exon 13 of 13	1		ENSP00000367858.3

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152070 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000438 AC: 110 AN: 250936 Hom.: 0 AF XY: 0.000442 AC XY: 60 AN XY: 135600

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000784

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.000264 AC: 386 AN: 1461700 Hom.: 0 Cov.: 31 AF XY: 0.000279 AC XY: 203 AN XY: 727112

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.00107

Gnomad4 ASJ exome AF: 0.000689

Gnomad4 EAS exome AF: 0.000378

Gnomad4 SAS exome AF: 0.000846

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000172

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74404

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000230 Hom.: 0

Bravo AF: 0.000249

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome Benign:2

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jan 22, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

AFF4-related disorder Benign:1

Jan 31, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	8.6
DANN	Benign	0.70
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7

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: rs138116584; hg19: chr5-132228048;