Genetic Variant AFF2:p.Arg22Cys (chrX-148652015-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_002025.4(AFF2):c.64C>T(p.Arg22Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000108 in 1,198,868 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000011 ( 0 hom. 1 hem. )

Consequence

AFF2
NM_002025.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.76

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

FRAXE intellectual disability
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
non-syndromic X-linked intellectual disability
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen

AFF2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.831

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFF2	NM_002025.4 link	c.64C>T	p.Arg22Cys	missense_variant	Exon 2 of 21	ENST00000370460.7	NP_002016.2	P51816-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AFF2	ENST00000370460.7 link	c.64C>T	p.Arg22Cys	missense_variant	Exon 2 of 21	5	NM_002025.4	ENSP00000359489.2	P51816-1
AFF2	ENST00000342251.7 link	c.64C>T	p.Arg22Cys	missense_variant	Exon 2 of 20	1		ENSP00000345459.4	P51816-3
AFF2	ENST00000370457.9 link	c.64C>T	p.Arg22Cys	missense_variant	Exon 2 of 20	1		ENSP00000359486.6	P51816-6
AFF2	ENST00000370458.5 link	c.64C>T	p.Arg22Cys	missense_variant	Exon 2 of 8	1		ENSP00000359487.1	P51816-4

Frequencies

GnomAD3 genomes

AF:

0.00000904

AC:

AN:

110591

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000329

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:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000113

AC:

AN:

176742

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000383

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000125

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1088277

Hom.:

Cov.:

AF XY:

0.00000282

AC XY:

AN XY:

354669

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

26103

American (AMR)

AF:

0.0000865

AC:

AN:

34666

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19127

East Asian (EAS)

AF:

0.00

AC:

AN:

30000

South Asian (SAS)

AF:

0.00

AC:

AN:

52573

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40354

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4101

European-Non Finnish (NFE)

AF:

0.00000957

AC:

AN:

835662

Other (OTH)

AF:

0.0000219

AC:

AN:

45691

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000103), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.398

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000904

AC:

AN:

110591

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32889

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000329

AC:

AN:

30392

American (AMR)

AF:

0.00

AC:

AN:

10382

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2632

East Asian (EAS)

AF:

0.00

AC:

AN:

3536

South Asian (SAS)

AF:

0.00

AC:

AN:

2554

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5878

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52812

Other (OTH)

AF:

0.00

AC:

AN:

1483

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Mar 31, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.47

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.87

D;.;.;.

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.83

D;D;D;D

MetaSVM

Uncertain

0.19

MutationAssessor

Pathogenic

3.1

M;M;M;M

PhyloP100

4.8

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-6.1

D;D;D;D

REVEL

Pathogenic

0.81

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

0.89

P;P;D;P

Vest4

0.63

MVP

0.97

MPC

0.71

ClinPred

0.80

GERP RS

4.8

Varity_R

0.80

gMVP

0.89

Mutation Taster

=88/12

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

X-148652015-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over