X-148661916-A-C

Variant names:

• chrX-148661916-A-C
• rs1198708145
• NM_002025.4:c.189A>C

Variant summary

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

The NM_002025.4(AFF2):​c.189A>C​(p.Lys63Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000251 in 1,194,125 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: AFF2 NM_002025.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.30
• Publications: 2 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.189A>C	p.Lys63Asn	missense_variant	Exon 3 of 21	ENST00000370460.7	NP_002016.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFF2	ENST00000370460.7	c.189A>C	p.Lys63Asn	missense_variant	Exon 3 of 21	5	NM_002025.4	ENSP00000359489.2
AFF2	ENST00000342251.7	c.177A>C	p.Lys59Asn	missense_variant	Exon 3 of 20	1		ENSP00000345459.4
AFF2	ENST00000370457.9	c.189A>C	p.Lys63Asn	missense_variant	Exon 3 of 20	1		ENSP00000359486.6
AFF2	ENST00000370458.5	c.177A>C	p.Lys59Asn	missense_variant	Exon 3 of 8	1		ENSP00000359487.1

Frequencies

GnomAD3 genomes AF: 0.00000896 AC: 1 AN: 111584 Hom.: 0 Cov.: 23

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000185 AC: 2 AN: 1082541 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 352659

African (AFR) AF: 0.00 AC: 0 AN: 25608

American (AMR) AF: 0.00 AC: 0 AN: 33043

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18611

East Asian (EAS) AF: 0.00 AC: 0 AN: 30021

South Asian (SAS) AF: 0.00 AC: 0 AN: 52170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40157

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4039

European-Non Finnish (NFE) AF: 0.00000240 AC: 2 AN: 833556

Other (OTH) AF: 0.00 AC: 0 AN: 45336

GnomAD4 genome AF: 0.00000896 AC: 1 AN: 111584 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33730

African (AFR) AF: 0.00 AC: 0 AN: 30712

American (AMR) AF: 0.00 AC: 0 AN: 10481

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2644

East Asian (EAS) AF: 0.00 AC: 0 AN: 3547

South Asian (SAS) AF: 0.00 AC: 0 AN: 2641

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6004

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53133

Other (OTH) AF: 0.00 AC: 0 AN: 1501

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 07, 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 supports that this missense variant has a deleterious effect on 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	0.94
BayesDel_addAF	Benign	-0.0064	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;.;.;.
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Uncertain	0.66	D;D;D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Pathogenic	3.1	M;.;.;M
PhyloP100		4.3
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.9	D;D;D;.
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	D;D;D;.
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.30
MutPred		0.79		Loss of ubiquitination at K63 (P = 0.013);.;.;Loss of ubiquitination at K63 (P = 0.013);
MVP		0.94
MPC		0.66
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.90
gMVP		0.78
Mutation Taster		=42/58	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

dbSNP: rs1198708145; hg19: chrX-147743437;