Genetic Variant AFF2:p.Tyr60Cys (chrX-148652130-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PP3BP6

The NM_002025.4(AFF2):c.179A>G(p.Tyr60Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y60H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Consequence

AFF2
NM_002025.4 missense, splice_region

Scores

Splicing: ADA: 0.9792

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.694

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, Labcorp Genetics (formerly Invitae), G2P
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;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BP6

Variant X-148652130-A-G is Benign according to our data. Variant chrX-148652130-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 975323.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002025.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AFF2	NM_002025.4	MANE Select	c.179A>G	p.Tyr60Cys	missense splice_region	Exon 2 of 21	NP_002016.2	P51816-1
AFF2	NM_001169124.2		c.179A>G	p.Tyr60Cys	missense splice_region	Exon 2 of 20	NP_001162595.1	P51816-6
AFF2	NM_001169123.2		c.168+11A>G		intron	N/A	NP_001162594.1	P51816-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AFF2	ENST00000370460.7	TSL:5 MANE Select	c.179A>G	p.Tyr60Cys	missense splice_region	Exon 2 of 21	ENSP00000359489.2	P51816-1
AFF2	ENST00000370457.9	TSL:1	c.179A>G	p.Tyr60Cys	missense splice_region	Exon 2 of 20	ENSP00000359486.6	P51816-6
AFF2	ENST00000342251.7	TSL:1	c.168+11A>G		intron	N/A	ENSP00000345459.4	P51816-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.63

M_CAP

Benign

0.062

MetaRNN

Benign

0.079

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.9

PhyloP100

0.69

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.67

REVEL

Benign

0.10

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.051

Polyphen

0.014

Vest4

0.16

MutPred

0.47

Loss of ubiquitination at K63 (P = 0.1083)

MVP

0.37

MPC

0.67

ClinPred

0.60

GERP RS

4.2

Varity_R

0.32

gMVP

0.10

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.79

SpliceAI score (max)

0.040

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over