dbSNP rs372514798: 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.

rs372514798

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