X-148652129-T-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002025.4(AFF2):c.178T>C(p.Tyr60His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,186,144 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y60C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000014 ( 0 hom. 6 hem. )

Consequence

AFF2
NM_002025.4 missense, splice_region

Scores

Splicing: ADA: 0.003907

Clinical Significance

Uncertain significance criteria provided, single submitter U:3

Conservation

PhyloP100: 1.65

Publications

0 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20219377).

BS2

High Hemizygotes in GnomAdExome4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFF2	NM_002025.4 link	c.178T>C	p.Tyr60His	missense_variant, splice_region_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.178T>C	p.Tyr60His	missense_variant, splice_region_variant	Exon 2 of 21	5	NM_002025.4	ENSP00000359489.2	P51816-1
AFF2	ENST00000370457.9 link	c.178T>C	p.Tyr60His	missense_variant, splice_region_variant	Exon 2 of 20	1		ENSP00000359486.6	P51816-6
AFF2	ENST00000342251.7 link	c.168+10T>C		intron_variant	Intron 2 of 19	1		ENSP00000345459.4	P51816-3
AFF2	ENST00000370458.5 link	c.168+10T>C		intron_variant	Intron 2 of 7	1		ENSP00000359487.1	P51816-4

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111867

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000140

AC:

AN:

1074277

Hom.:

Cov.:

AF XY:

0.0000175

AC XY:

AN XY:

343123

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25537

American (AMR)

AF:

0.00

AC:

AN:

32559

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18690

East Asian (EAS)

AF:

0.00

AC:

AN:

30051

South Asian (SAS)

AF:

0.00

AC:

AN:

51386

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40365

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4033

European-Non Finnish (NFE)

AF:

0.0000181

AC:

AN:

826471

Other (OTH)

AF:

0.00

AC:

AN:

45185

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000179

AC:

AN:

111867

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34035

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

30784

American (AMR)

AF:

0.00

AC:

AN:

10519

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2646

East Asian (EAS)

AF:

0.00

AC:

AN:

3574

South Asian (SAS)

AF:

0.00

AC:

AN:

2655

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6096

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.0000376

AC:

AN:

53166

Other (OTH)

AF:

0.00

AC:

AN:

1507

⚠️ 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: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 07, 2019

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

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

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Benign

-0.073

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

T;.

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.54

T;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.20

T;T

MetaSVM

Benign

-0.72

MutationAssessor

Benign

1.5

L;L

PhyloP100

1.7

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.22

N;.

REVEL

Benign

0.20

Sift

Uncertain

0.0010

D;.

Sift4G

Benign

0.25

T;T

Polyphen

0.93

P;P

Vest4

0.16

MutPred

0.51

Gain of disorder (P = 0.0433);Gain of disorder (P = 0.0433);

MVP

0.46

MPC

0.67

ClinPred

0.64

GERP RS

5.3

Varity_R

0.25

gMVP

0.11

Mutation Taster

=80/20

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0039

dbscSNV1_RF

Benign

0.090

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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X-148652129-T-C

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