X-148501128-G-A

Variant names:

• chrX-148501128-G-A
• rs2052343731
• NM_002025.4:c.31G>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.31G>A​(p.Asp11Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000165 in 1,209,934 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: AFF2 NM_002025.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.80
• 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=0.33192158).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFF2	NM_002025.4	c.31G>A	p.Asp11Asn	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.31G>A	p.Asp11Asn	missense_variant	Exon 1 of 21	5	NM_002025.4	ENSP00000359489.2
AFF2	ENST00000342251.7	c.31G>A	p.Asp11Asn	missense_variant	Exon 1 of 20	1		ENSP00000345459.4
AFF2	ENST00000370457.9	c.31G>A	p.Asp11Asn	missense_variant	Exon 1 of 20	1		ENSP00000359486.6
AFF2	ENST00000370458.5	c.31G>A	p.Asp11Asn	missense_variant	Exon 1 of 8	1		ENSP00000359487.1

Frequencies

GnomAD3 genomes AF: 0.00000888 AC: 1 AN: 112561 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000161

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097373 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 362937

African (AFR) AF: 0.00 AC: 0 AN: 26369

American (AMR) AF: 0.00 AC: 0 AN: 35175

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19344

East Asian (EAS) AF: 0.00 AC: 0 AN: 30162

South Asian (SAS) AF: 0.00 AC: 0 AN: 54111

European-Finnish (FIN) AF: 0.0000248 AC: 1 AN: 40392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4130

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841645

Other (OTH) AF: 0.00 AC: 0 AN: 46045

GnomAD4 genome AF: 0.00000888 AC: 1 AN: 112561 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34721

African (AFR) AF: 0.00 AC: 0 AN: 30977

American (AMR) AF: 0.00 AC: 0 AN: 10779

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2660

East Asian (EAS) AF: 0.00 AC: 0 AN: 3552

South Asian (SAS) AF: 0.00 AC: 0 AN: 2702

European-Finnish (FIN) AF: 0.000161 AC: 1 AN: 6224

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53232

Other (OTH) AF: 0.00 AC: 0 AN: 1510

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Feb 28, 2023

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 supports 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	Pathogenic	0.66
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T;.;.;.
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.78	T;T;T;T
M_CAP	Pathogenic	0.73	D
MetaRNN	Benign	0.33	T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.69	N;N;N;N
PhyloP100		5.8
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.16	N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.29	T;T;T;T
Sift4G	Benign	0.32	T;T;T;T
Polyphen		0.46	P;P;P;P
Vest4		0.30
MutPred		0.45		Loss of disorder (P = 0.0627);Loss of disorder (P = 0.0627);Loss of disorder (P = 0.0627);Loss of disorder (P = 0.0627);
MVP		0.63
MPC		0.19
ClinPred		0.83	D
GERP RS		4.2
PromoterAI		0.025	Neutral
Varity_R		0.22
gMVP		0.13
Mutation Taster		=83/17	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

dbSNP: rs2052343731; hg19: chrX-147582648;