NM_002025.4:c.164A>G

Variant names:

• chrX-148652115-A-G
• NM_002025.4:c.164A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PP3_Strong BS2

The NM_002025.4(AFF2):​c.164A>G​(p.Tyr55Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000184 in 1,086,669 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 2 hem.)
• Consequence: AFF2 NM_002025.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.97
• 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002025.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFF2	NM_002025.4	MANE Select	c.164A>G	p.Tyr55Cys	missense	Exon 2 of 21	NP_002016.2	P51816-1
	AFF2	NM_001169123.2		c.164A>G	p.Tyr55Cys	missense	Exon 2 of 21	NP_001162594.1	P51816-5
	AFF2	NM_001169122.2		c.164A>G	p.Tyr55Cys	missense	Exon 2 of 20	NP_001162593.1	P51816-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFF2	ENST00000370460.7	TSL:5 MANE Select	c.164A>G	p.Tyr55Cys	missense	Exon 2 of 21	ENSP00000359489.2	P51816-1
	AFF2	ENST00000342251.7	TSL:1	c.164A>G	p.Tyr55Cys	missense	Exon 2 of 20	ENSP00000345459.4	P51816-3
	AFF2	ENST00000370457.9	TSL:1	c.164A>G	p.Tyr55Cys	missense	Exon 2 of 20	ENSP00000359486.6	P51816-6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000184 AC: 2 AN: 1086669 Hom.: 0 Cov.: 26 AF XY: 0.00000567 AC XY: 2 AN XY: 352737

African (AFR) AF: 0.00 AC: 0 AN: 26066

American (AMR) AF: 0.00 AC: 0 AN: 34275

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19088

East Asian (EAS) AF: 0.00 AC: 0 AN: 30121

South Asian (SAS) AF: 0.00 AC: 0 AN: 52592

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40469

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4094

European-Non Finnish (NFE) AF: 0.00000240 AC: 2 AN: 834292

Other (OTH) AF: 0.00 AC: 0 AN: 45672

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		9.0
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.89		Gain of catalytic residue at P54 (P = 0.0135)
MVP		0.90
MPC		0.68
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.92
gMVP		0.77
Mutation Taster		=31/69	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-147733636;