chrX-148652130-A-G

Variant names:

• chrX-148652130-A-G
• rs2054208783
• NM_002025.4:c.179A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP3 BP6

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

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 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 id is 975323.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFF2	NM_002025.4	c.179A>G	p.Tyr60Cys	missense_variant, splice_region_variant	Exon 2 of 21	ENST00000370460.7	NP_002016.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFF2	ENST00000370460.7	c.179A>G	p.Tyr60Cys	missense_variant, splice_region_variant	Exon 2 of 21	5	NM_002025.4	ENSP00000359489.2
AFF2	ENST00000370457.9	c.179A>G	p.Tyr60Cys	missense_variant, splice_region_variant	Exon 2 of 20	1		ENSP00000359486.6
AFF2	ENST00000342251.7	c.168+11A>G		intron_variant	Intron 2 of 19	1		ENSP00000345459.4
AFF2	ENST00000370458.5	c.168+11A>G		intron_variant	Intron 2 of 7	1		ENSP00000359487.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Intellectual disability Benign:1

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;.
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.63	T;T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.079	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.9	L;L
PhyloP100		0.69
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.67	N;.
REVEL	Benign	0.10
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.051	T;T
Polyphen		0.014	B;B
Vest4		0.16
MutPred		0.47		Loss of ubiquitination at K63 (P = 0.1083);Loss of ubiquitination at K63 (P = 0.1083);
MVP		0.37
MPC		0.67
ClinPred		0.60	D
GERP RS		4.2
Varity_R		0.32
gMVP		0.10
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs2054208783; hg19: chrX-147733651;