rs140927355

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002025.4(AFF2):c.2780G>A(p.Arg927His) variant causes a missense change. The variant allele was found at a frequency of 0.00101 in 1,208,209 control chromosomes in the GnomAD database, including 2 homozygotes. There are 482 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00080 ( 0 hom., 29 hem., cov: 23)

Exomes 𝑓: 0.0010 ( 2 hom. 453 hem. )

Consequence

AFF2
NM_002025.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 3.61

Variant links:

Genes affected

AFF2 (HGNC:3776): (ALF transcription elongation factor 2) This gene encodes a putative transcriptional activator that is a member of the AF4\FMR2 gene family. This gene is associated with the folate-sensitive fragile X E locus on chromosome X. A repeat polymorphism in the fragile X E locus results in silencing of this gene causing Fragile X E syndrome. Fragile X E syndrome is a form of nonsyndromic X-linked cognitive disability. In addition, this gene contains 6-25 GCC repeats that are expanded to >200 repeats in the disease state. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Jul 2016]

AFF2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0070457757).

BP6

Variant X-148962804-G-A is Benign according to our data. Variant chrX-148962804-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 194202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-148962804-G-A is described in Lovd as [Benign]. Variant chrX-148962804-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000804 (90/111989) while in subpopulation SAS AF= 0.0034 (9/2649). AF 95% confidence interval is 0.00177. There are 0 homozygotes in gnomad4. There are 29 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 29 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFF2	NM_002025.4 link	c.2780G>A	p.Arg927His	missense_variant	Exon 13 of 21	ENST00000370460.7	NP_002016.2	P51816-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFF2	ENST00000370460.7 link	c.2780G>A	p.Arg927His	missense_variant	Exon 13 of 21	5	NM_002025.4	ENSP00000359489.2		P51816-1

Frequencies

GnomAD3 genomes

AF:

0.000804

AC:

AN:

111939

Hom.:

Cov.:

AF XY:

0.000850

AC XY:

AN XY:

34125

show subpopulations

Gnomad AFR

AF:

0.0000325

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000285

Gnomad ASJ

AF:

0.0170

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00339

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000564

Gnomad OTH

AF:

0.00132

GnomAD3 exomes

AF:

0.00170

AC:

311

AN:

183174

Hom.:

AF XY:

0.00197

AC XY:

133

AN XY:

67672

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000475

Gnomad ASJ exome

AF:

0.0169

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00488

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000758

Gnomad OTH exome

AF:

0.00376

GnomAD4 exome

AF:

0.00103

AC:

1126

AN:

1096220

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

453

AN XY:

361702

show subpopulations

Gnomad4 AFR exome

AF:

0.000417

Gnomad4 AMR exome

AF:

0.000568

Gnomad4 ASJ exome

AF:

0.0171

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.00544

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000447

Gnomad4 OTH exome

AF:

0.00182

GnomAD4 genome

AF:

0.000804

AC:

AN:

111989

Hom.:

Cov.:

AF XY:

0.000848

AC XY:

AN XY:

34185

show subpopulations

Gnomad4 AFR

AF:

0.0000324

Gnomad4 AMR

AF:

0.000285

Gnomad4 ASJ

AF:

0.0170

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00340

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000564

Gnomad4 OTH

AF:

0.00131

Alfa

AF:

0.00137

Hom.:

Bravo

AF:

0.000861

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000892

AC:

ExAC

AF:

0.00165

AC:

200

EpiCase

AF:

0.000927

EpiControl

AF:

0.000830

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

AFF2: BP4, BS1, BS2 -

not specified

Benign:2

Jul 20, 2015

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 21, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

FRAXE

Benign:2

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 14, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

AFF2-related disorder

Benign:1

May 20, 2021

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

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.073

BayesDel_noAF

Uncertain

0.12

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.41

T;.;.;.

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.87

D;D;D;D

M_CAP

Pathogenic

0.79

MetaRNN

Benign

0.0070

T;T;T;T

MetaSVM

Uncertain

-0.18

MutationAssessor

Uncertain

2.1

M;.;.;.

PrimateAI

Benign

0.42

PROVEAN

Benign

0.13

N;N;.;N

REVEL

Benign

0.29

Sift

Uncertain

0.0030

D;D;.;D

Sift4G

Benign

0.23

T;T;T;T

Polyphen

1.0

D;D;D;.

Vest4

0.059

MVP

0.93

MPC

0.65

ClinPred

0.042

GERP RS

5.9

Varity_R

0.19

gMVP

0.32

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

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