chrX-148501105-T-C

Variant names:

• chrX-148501105-T-C
• NM_002025.4:c.8T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002025.4(AFF2):​c.8T>C​(p.Leu3Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: AFF2 NM_002025.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.41
• 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFF2	NM_002025.4	c.8T>C	p.Leu3Pro	missense_variant	Exon 1 of 21	ENST00000370460.7	NP_002016.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFF2	ENST00000370460.7	c.8T>C	p.Leu3Pro	missense_variant	Exon 1 of 21	5	NM_002025.4	ENSP00000359489.2
AFF2	ENST00000342251.7	c.8T>C	p.Leu3Pro	missense_variant	Exon 1 of 20	1		ENSP00000345459.4
AFF2	ENST00000370457.9	c.8T>C	p.Leu3Pro	missense_variant	Exon 1 of 20	1		ENSP00000359486.6
AFF2	ENST00000370458.5	c.8T>C	p.Leu3Pro	missense_variant	Exon 1 of 8	1		ENSP00000359487.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Apr 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.8T>C (p.L3P) alteration is located in exon 1 (coding exon 1) of the AFF2 gene. This alteration results from a T to C substitution at nucleotide position 8, causing the leucine (L) at amino acid position 3 to be replaced by a proline (P). 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	0.91
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;.;.;.
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.66	T;T;T;T
M_CAP	Pathogenic	0.91	D
MetaRNN	Uncertain	0.68	D;D;D;D
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.90	L;L;L;L
PhyloP100		4.4
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Benign	0.26
Sift	Benign	0.072	T;T;T;T
Sift4G	Benign	0.17	T;T;D;T
Polyphen		1.0	D;D;D;D
Vest4		0.56
MutPred		0.29		Loss of stability (P = 0.0038);Loss of stability (P = 0.0038);Loss of stability (P = 0.0038);Loss of stability (P = 0.0038);
MVP		0.84
MPC		0.77
ClinPred		0.87	D
GERP RS		3.5
PromoterAI		0.040	Neutral
Varity_R		0.72
gMVP		0.91
Mutation Taster		=48/52	disease causing

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-147582625;