X-148652095-T-A

Variant names:

• chrX-148652095-T-A
• NM_002025.4:c.144T>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.144T>A​(p.Phe48Leu) 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 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: 23)
• Consequence: AFF2 NM_002025.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.72
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40128).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFF2	NM_002025.4	c.144T>A	p.Phe48Leu	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.144T>A	p.Phe48Leu	missense_variant	Exon 2 of 21	5	NM_002025.4	ENSP00000359489.2
AFF2	ENST00000342251.7	c.144T>A	p.Phe48Leu	missense_variant	Exon 2 of 20	1		ENSP00000345459.4
AFF2	ENST00000370457.9	c.144T>A	p.Phe48Leu	missense_variant	Exon 2 of 20	1		ENSP00000359486.6
AFF2	ENST00000370458.5	c.144T>A	p.Phe48Leu	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

Inborn genetic diseases Uncertain:1

Sep 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.144T>A (p.F48L) alteration is located in exon 2 (coding exon 2) of the AFF2 gene. This alteration results from a T to A substitution at nucleotide position 144, causing the phenylalanine (F) at amino acid position 48 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;.;.;.
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.84	T;T;T;T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.40	T;T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.3	M;M;M;M
PhyloP100		1.7
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.4	D;D;D;D
REVEL	Uncertain	0.40
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		0.56
MPC		0.64
ClinPred		0.99	D
GERP RS		3.2
Varity_R		0.62
gMVP		0.42
Mutation Taster		=69/31	polymorphism

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

Other links and lift over

hg19: chrX-147733616;