X-148980756-G-T

Variant names:

• chrX-148980756-G-T
• rs373659849
• NM_002025.4:c.3589G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002025.4(AFF2):​c.3589G>T​(p.Ala1197Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000277 in 1,083,450 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1197T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000028 (0 hom. 1 hem.)
• Consequence: AFF2 NM_002025.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.471
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05122909).

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.3589G>T	p.Ala1197Ser	missense	Exon 19 of 21	NP_002016.2
	AFF2	NM_001169123.2		c.3559G>T	p.Ala1187Ser	missense	Exon 19 of 21	NP_001162594.1
	AFF2	NM_001169122.2		c.3484G>T	p.Ala1162Ser	missense	Exon 18 of 20	NP_001162593.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFF2	ENST00000370460.7	TSL:5 MANE Select	c.3589G>T	p.Ala1197Ser	missense	Exon 19 of 21	ENSP00000359489.2
	AFF2	ENST00000342251.7	TSL:1	c.3484G>T	p.Ala1162Ser	missense	Exon 18 of 20	ENSP00000345459.4
	AFF2	ENST00000370457.9	TSL:1	c.3484G>T	p.Ala1162Ser	missense	Exon 18 of 20	ENSP00000359486.6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000277 AC: 3 AN: 1083450 Hom.: 0 Cov.: 26 AF XY: 0.00000285 AC XY: 1 AN XY: 350882

African (AFR) AF: 0.00 AC: 0 AN: 26135

American (AMR) AF: 0.00 AC: 0 AN: 34840

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18934

East Asian (EAS) AF: 0.00 AC: 0 AN: 29647

South Asian (SAS) AF: 0.00 AC: 0 AN: 52737

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4059

European-Non Finnish (NFE) AF: 0.00000360 AC: 3 AN: 832248

Other (OTH) AF: 0.00 AC: 0 AN: 45258

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.045
DANN	Benign	0.68
DEOGEN2	Benign	0.19	T
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.47
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.12
Sift	Benign	0.50	T
Sift4G	Benign	0.85	T
Polyphen		0.0070	B
Vest4		0.055
MutPred		0.61		Gain of disorder (P = 0.0267)
MVP		0.45
MPC		0.74
ClinPred		0.047	T
GERP RS		-8.7
Varity_R		0.063
gMVP		0.44
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs373659849; hg19: chrX-148062286;