NM_002025.4:c.2702C>A

Variant names:

• chrX-148962726-C-A
• rs782757734
• NM_002025.4:c.2702C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002025.4(AFF2):​c.2702C>A​(p.Ser901Tyr) variant causes a missense 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. 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. S901F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: AFF2 NM_002025.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.62
• Publications: 1 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39437324).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFF2	NM_002025.4	c.2702C>A	p.Ser901Tyr	missense_variant	Exon 13 of 21	ENST00000370460.7	NP_002016.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFF2	ENST00000370460.7	c.2702C>A	p.Ser901Tyr	missense_variant	Exon 13 of 21	5	NM_002025.4	ENSP00000359489.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 17, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D;.;.;.
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.86	D;D;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Benign	0.39	T;T;T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.7	M;.;.;.
PhyloP100		2.6
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-2.7	D;D;.;D
REVEL	Benign	0.25
Sift	Uncertain	0.020	D;D;.;D
Sift4G	Uncertain	0.031	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.13
MutPred		0.29		Loss of glycosylation at S901 (P = 0.0898);.;.;.;
MVP		0.63
MPC		0.69
ClinPred		0.95	D
GERP RS		5.0
Varity_R		0.35
gMVP		0.30
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs782757734; hg19: chrX-148044256;