chr5-132892441-A-G

Variant names:

• chr5-132892441-A-G
• rs11739417
• NM_014423.4:c.2397-37T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014423.4(AFF4):​c.2397-37T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 1,582,724 control chromosomes in the GnomAD database, including 30,518 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3535 hom., cov: 32)
  • Exomes 𝑓: 0.19 (26983 hom.)
• Consequence: AFF4 NM_014423.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.293
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

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

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Illumina

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 5-132892441-A-G is Benign according to our data. Variant chr5-132892441-A-G is described in ClinVar as Benign. ClinVar VariationId is 1248920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.282 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014423.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFF4	NM_014423.4	MANE Select	c.2397-37T>C		intron	N/A	NP_055238.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFF4	ENST00000265343.10	TSL:1 MANE Select	c.2397-37T>C		intron	N/A	ENSP00000265343.5
	AFF4	ENST00000378595.7	TSL:1	c.2397-37T>C		intron	N/A	ENSP00000367858.3

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31378 AN: 151982 Hom.: 3527 Cov.: 32

Gnomad AFR AF: 0.286

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.190

Gnomad EAS AF: 0.140

Gnomad SAS AF: 0.0848

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.220

Gnomad NFE AF: 0.198

Gnomad OTH AF: 0.223

GnomAD2 exomes AF: 0.167 AC: 38238 AN: 228466 AF XY: 0.164

Gnomad AFR exome AF: 0.294

Gnomad AMR exome AF: 0.115

Gnomad ASJ exome AF: 0.208

Gnomad EAS exome AF: 0.145

Gnomad FIN exome AF: 0.101

Gnomad NFE exome AF: 0.197

Gnomad OTH exome AF: 0.182

GnomAD4 exome AF: 0.190 AC: 271303 AN: 1430624 Hom.: 26983 Cov.: 33 AF XY: 0.188 AC XY: 133082 AN XY: 708410

African (AFR) AF: 0.302 AC: 9762 AN: 32370

American (AMR) AF: 0.120 AC: 4853 AN: 40326

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 4915 AN: 24382

East Asian (EAS) AF: 0.129 AC: 5076 AN: 39318

South Asian (SAS) AF: 0.0927 AC: 7641 AN: 82410

European-Finnish (FIN) AF: 0.107 AC: 5589 AN: 52224

Middle Eastern (MID) AF: 0.186 AC: 871 AN: 4680

European-Non Finnish (NFE) AF: 0.202 AC: 221214 AN: 1096140

Other (OTH) AF: 0.194 AC: 11382 AN: 58774

GnomAD4 genome AF: 0.207 AC: 31411 AN: 152100 Hom.: 3535 Cov.: 32 AF XY: 0.199 AC XY: 14833 AN XY: 74382

African (AFR) AF: 0.286 AC: 11850 AN: 41458

American (AMR) AF: 0.165 AC: 2529 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 659 AN: 3472

East Asian (EAS) AF: 0.140 AC: 726 AN: 5186

South Asian (SAS) AF: 0.0853 AC: 412 AN: 4830

European-Finnish (FIN) AF: 0.101 AC: 1066 AN: 10586

Middle Eastern (MID) AF: 0.229 AC: 67 AN: 292

European-Non Finnish (NFE) AF: 0.198 AC: 13466 AN: 67968

Other (OTH) AF: 0.220 AC: 465 AN: 2114

Alfa AF: 0.134 Hom.: 336

Bravo AF: 0.217

Asia WGS AF: 0.106 AC: 369 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

May 08, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.4
DANN	Benign	0.62
PhyloP100		0.29
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs11739417; hg19: chr5-132228133; COSMIC: COSV54791607; COSMIC: COSV54791607;