Variant rs755428630 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1PM4_SupportingBS2

The NM_014423.4(AFF4):c.516_518dupACA(p.Glu172_His173insGln) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.0000192 in 1,614,158 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 1 hom. )

Consequence

AFF4
NM_014423.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 4.21

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 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

PM4

Nonframeshift variant in NON repetitive region in NM_014423.4. Strenght limited to Supporting due to length of the change: 1aa.

BS2

High AC in GnomAdExome4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFF4	NM_014423.4 link	c.516_518dupACA	p.Glu172_His173insGln	disruptive_inframe_insertion	Exon 3 of 21	ENST00000265343.10	NP_055238.1	Q9UHB7-1
AFF4	XM_005271963.6 link	c.516_518dupACA	p.Glu172_His173insGln	disruptive_inframe_insertion	Exon 4 of 22		XP_005272020.1	Q9UHB7-1
AFF4	XM_006714587.5 link	c.516_518dupACA	p.Glu172_His173insGln	disruptive_inframe_insertion	Exon 3 of 20		XP_006714650.1
AFF4	XM_047417103.1 link	c.516_518dupACA	p.Glu172_His173insGln	disruptive_inframe_insertion	Exon 4 of 21		XP_047273059.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AFF4	ENST00000265343.10 link	c.516_518dupACA	p.Glu172_His173insGln	disruptive_inframe_insertion	Exon 3 of 21	1	NM_014423.4	ENSP00000265343.5	Q9UHB7-1
AFF4	ENST00000378595.7 link	c.516_518dupACA	p.Glu172_His173insGln	disruptive_inframe_insertion	Exon 3 of 13	1		ENSP00000367858.3	Q9UHB7-2
AFF4	ENST00000465484.1 link	n.775_777dupACA		non_coding_transcript_exon_variant	Exon 3 of 5	1
AFF4	ENST00000491831.5 link	n.776_778dupACA		non_coding_transcript_exon_variant	Exon 3 of 7	1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 29, 2024

This variant, c.516_518dup, results in the insertion of 1 amino acid(s) of the AFF4 protein (p.Glu172_His173insGln), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with AFF4-related conditions. ClinVar contains an entry for this variant (Variation ID: 591050). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over