Variant 2-99554313-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001386135.1(AFF3):c.3557G>A(p.Arg1186Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000585 in 1,614,170 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.00060 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00058 ( 2 hom. )

Consequence

AFF3
NM_001386135.1 missense, splice_region

Scores

Splicing: ADA: 0.8991

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 3.38

Variant links:

Genes affected

AFF3 (HGNC:6473): (ALF transcription elongation factor 3) This gene encodes a tissue-restricted nuclear transcriptional activator that is preferentially expressed in lymphoid tissue. Isolation of this protein initially defined a highly conserved LAF4/MLLT2 gene family of nuclear transcription factors that may function in lymphoid development and oncogenesis. In some ALL patients, this gene has been found fused to the gene for MLL. Multiple alternatively spliced transcript variants that encode different proteins have been found for this gene. [provided by RefSeq, Jul 2008]

AFF3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0074131787).

BP6

Variant 2-99554313-C-T is Benign according to our data. Variant chr2-99554313-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3352584.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAd4 at 92 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AFF3	NM_001386135.1 linkuse as main transcript	c.3557G>A	p.Arg1186Gln	missense_variant, splice_region_variant	24/25	ENST00000672756.2	NP_001373064.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AFF3	ENST00000672756.2 linkuse as main transcript	c.3557G>A	p.Arg1186Gln	missense_variant, splice_region_variant	24/25		NM_001386135.1	ENSP00000500419	A2	P51826-1

Frequencies

GnomAD3 genomes

AF:

0.000598

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000852

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000494

AC:

124

AN:

250974

Hom.:

AF XY:

0.000545

AC XY:

AN XY:

135662

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00157

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000556

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000584

AC:

853

AN:

1461852

Hom.:

Cov.:

AF XY:

0.000578

AC XY:

420

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.00138

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000614

Gnomad4 OTH exome

AF:

0.000530

GnomAD4 genome

AF:

0.000604

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000853

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000578

Hom.:

Bravo

AF:

0.000559

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000634

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000654

EpiControl

AF:

0.000771

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

AFF3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 15, 2024

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

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.059

T;T;.

Eigen

Benign

0.13

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.88

.;D;D

M_CAP

Benign

0.018

MetaRNN

Benign

0.0074

T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

1.2

L;L;.

MutationTaster

Benign

0.94

D;D;D;D

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.4

N;N;N

REVEL

Benign

0.15

Sift

Benign

0.13

T;T;T

Sift4G

Benign

0.19

T;T;T

Polyphen

0.30

B;B;P

Vest4

0.31

MVP

0.27

ClinPred

0.026

GERP RS

5.5

Varity_R

0.14

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.90

dbscSNV1_RF

Pathogenic

0.74

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

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