X-148652094-T-A

Variant names:

• chrX-148652094-T-A
• NM_002025.4:c.143T>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002025.4(AFF2):​c.143T>A​(p.Phe48Tyr) variant causes a missense change. 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 (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: AFF2 NM_002025.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.94

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30623126).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFF2	NM_002025.4	c.143T>A	p.Phe48Tyr	missense_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.143T>A	p.Phe48Tyr	missense_variant	Exon 2 of 21	5	NM_002025.4	ENSP00000359489.2
AFF2	ENST00000342251.7	c.143T>A	p.Phe48Tyr	missense_variant	Exon 2 of 20	1		ENSP00000345459.4
AFF2	ENST00000370457.9	c.143T>A	p.Phe48Tyr	missense_variant	Exon 2 of 20	1		ENSP00000359486.6
AFF2	ENST00000370458.5	c.143T>A	p.Phe48Tyr	missense_variant	Exon 2 of 8	1		ENSP00000359487.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Aug 16, 2024

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 indicates that this missense variant does not alter 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	Uncertain	0.40
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.;.;.
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.53	T;T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.31	T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.4	L;L;L;L
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	0.17	N;N;N;N
REVEL	Benign	0.26
Sift	Benign	0.67	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		1.0	D;D;D;D
Vest4		0.36
MutPred		0.60		Loss of stability (P = 0.0166);Loss of stability (P = 0.0166);Loss of stability (P = 0.0166);Loss of stability (P = 0.0166);
MVP		0.65
MPC		0.64
ClinPred		0.91	D
GERP RS		4.4
Varity_R		0.31
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-147733615;