Genetic Variant AFF2:p.Phe48Leu (chrX-148652093-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002025.4(AFF2):c.142T>C(p.Phe48Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000918 in 1,089,058 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F48Y) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 9.2e-7 ( 0 hom. 1 hem. )

Consequence

AFF2
NM_002025.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.72

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFF2	NM_002025.4 link	c.142T>C	p.Phe48Leu	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.142T>C	p.Phe48Leu	missense_variant	Exon 2 of 21	5	NM_002025.4	ENSP00000359489.2	P51816-1
AFF2	ENST00000342251.7 link	c.142T>C	p.Phe48Leu	missense_variant	Exon 2 of 20	1		ENSP00000345459.4	P51816-3
AFF2	ENST00000370457.9 link	c.142T>C	p.Phe48Leu	missense_variant	Exon 2 of 20	1		ENSP00000359486.6	P51816-6
AFF2	ENST00000370458.5 link	c.142T>C	p.Phe48Leu	missense_variant	Exon 2 of 8	1		ENSP00000359487.1	P51816-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.18e-7

AC:

AN:

1089058

Hom.:

Cov.:

AF XY:

0.00000282

AC XY:

AN XY:

354754

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26203

American (AMR)

AF:

0.00

AC:

AN:

34988

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19289

East Asian (EAS)

AF:

0.00

AC:

AN:

30148

South Asian (SAS)

AF:

0.00

AC:

AN:

53489

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40503

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4108

European-Non Finnish (NFE)

AF:

0.00000120

AC:

AN:

834545

Other (OTH)

AF:

0.00

AC:

AN:

45785

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jun 28, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.014

BayesDel_noAF

Benign

-0.22

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.47

T;.;.;.

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.84

T;T;T;T

M_CAP

Pathogenic

0.32

MetaRNN

Uncertain

0.53

D;D;D;D

MetaSVM

Benign

-0.41

MutationAssessor

Uncertain

2.3

M;M;M;M

PhyloP100

7.7

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-3.4

D;D;D;D

REVEL

Uncertain

0.48

Sift

Uncertain

0.029

D;D;D;D

Sift4G

Benign

0.51

T;T;T;T

Polyphen

1.0

D;D;D;D

Vest4

0.43

MutPred

0.60

Loss of stability (P = 0.07);Loss of stability (P = 0.07);Loss of stability (P = 0.07);Loss of stability (P = 0.07);

MVP

0.53

MPC

0.64

ClinPred

0.99

GERP RS

5.6

Varity_R

0.69

gMVP

0.42

Mutation Taster

=39/61

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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chrX-148652093-T-C

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