rs200306870

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002025.4(AFF2):c.1121C>A(p.Ser374Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000312 in 1,199,259 control chromosomes in the GnomAD database, including 2 homozygotes. There are 125 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00031 ( 1 hom., 12 hem., cov: 22)

Exomes 𝑓: 0.00031 ( 1 hom. 113 hem. )

Consequence

AFF2
NM_002025.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.83

Publications

3 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008142501).

BP6

Variant X-148837681-C-A is Benign according to our data. Variant chrX-148837681-C-A is described in ClinVar as Benign. ClinVar VariationId is 197738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000314 (35/111561) while in subpopulation EAS AF = 0.00905 (32/3534). AF 95% confidence interval is 0.00659. There are 1 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 12 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFF2	NM_002025.4 link	c.1121C>A	p.Ser374Tyr	missense_variant	Exon 5 of 21	ENST00000370460.7	NP_002016.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFF2	ENST00000370460.7 link	c.1121C>A	p.Ser374Tyr	missense_variant	Exon 5 of 21	5	NM_002025.4	ENSP00000359489.2

Frequencies

GnomAD3 genomes

AF:

0.000314

AC:

AN:

111507

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00903

Gnomad SAS

AF:

0.000386

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000882

AC:

161

AN:

182529

AF XY:

0.000820

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0113

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000614

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000312

AC:

339

AN:

1087698

Hom.:

Cov.:

AF XY:

0.000319

AC XY:

113

AN XY:

353926

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26205

American (AMR)

AF:

0.00

AC:

AN:

35172

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19323

East Asian (EAS)

AF:

0.00922

AC:

278

AN:

30155

South Asian (SAS)

AF:

0.0000557

AC:

AN:

53869

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40493

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4110

European-Non Finnish (NFE)

AF:

0.0000312

AC:

AN:

832644

Other (OTH)

AF:

0.000700

AC:

AN:

45727

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000314

AC:

AN:

111561

Hom.:

Cov.:

AF XY:

0.000356

AC XY:

AN XY:

33735

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30714

American (AMR)

AF:

0.00

AC:

AN:

10496

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2650

East Asian (EAS)

AF:

0.00905

AC:

AN:

3534

South Asian (SAS)

AF:

0.000387

AC:

AN:

2584

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6024

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0000376

AC:

AN:

53128

Other (OTH)

AF:

0.00

AC:

AN:

1529

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000699

Hom.:

Bravo

AF:

0.000574

ExAC

AF:

0.000939

AC:

114

EpiCase

AF:

0.00

EpiControl

AF:

0.0000596

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 05, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Apr 16, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

AFF2-related disorder

Benign:1

Jul 12, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as 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

0.15

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.68

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.85

MetaRNN

Benign

0.0081

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.0

PhyloP100

1.8

PrimateAI

Benign

0.38

PROVEAN

Benign

-2.2

REVEL

Benign

0.16

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0030

Polyphen

0.73

Vest4

0.28

MVP

0.33

MPC

0.18

ClinPred

0.14

GERP RS

3.6

Varity_R

0.26

gMVP

0.45

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

1.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over