chrX-148980756-G-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_002025.4(AFF2):​c.3589G>A​(p.Ala1197Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000268 in 1,194,993 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 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. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., 7 hem., cov: 23)
  • Exomes 𝑓: 0.000018 (0 hom. 9 hem.)
• Consequence: AFF2 NM_002025.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• 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, Labcorp Genetics (formerly Invitae), G2P
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.032989204).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000117 (13/111550) while in subpopulation AFR AF = 0.000358 (11/30720). AF 95% confidence interval is 0.0002. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 7 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.3589G>A	p.Ala1197Thr	missense	Exon 19 of 21	NP_002016.2	P51816-1
	AFF2	NM_001169123.2		c.3559G>A	p.Ala1187Thr	missense	Exon 19 of 21	NP_001162594.1	P51816-5
	AFF2	NM_001169122.2		c.3484G>A	p.Ala1162Thr	missense	Exon 18 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.3589G>A	p.Ala1197Thr	missense	Exon 19 of 21	ENSP00000359489.2	P51816-1
	AFF2	ENST00000342251.7	TSL:1	c.3484G>A	p.Ala1162Thr	missense	Exon 18 of 20	ENSP00000345459.4	P51816-3
	AFF2	ENST00000370457.9	TSL:1	c.3484G>A	p.Ala1162Thr	missense	Exon 18 of 20	ENSP00000359486.6	P51816-6

Frequencies

GnomAD3 genomes AF: 0.000117 AC: 13 AN: 111496 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000359

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000956

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000279

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000384 AC: 7 AN: 182519 AF XY: 0.0000597

Gnomad AFR exome AF: 0.0000761

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000725

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000367

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000175 AC: 19 AN: 1083443 Hom.: 0 Cov.: 26 AF XY: 0.0000257 AC XY: 9 AN XY: 350875

African (AFR) AF: 0.000115 AC: 3 AN: 26134

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

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

East Asian (EAS) AF: 0.000101 AC: 3 AN: 29647

South Asian (SAS) AF: 0.000114 AC: 6 AN: 52736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39593

Middle Eastern (MID) AF: 0.000246 AC: 1 AN: 4059

European-Non Finnish (NFE) AF: 0.00000601 AC: 5 AN: 832243

Other (OTH) AF: 0.0000221 AC: 1 AN: 45257

GnomAD4 genome AF: 0.000117 AC: 13 AN: 111550 Hom.: 0 Cov.: 23 AF XY: 0.000207 AC XY: 7 AN XY: 33836

African (AFR) AF: 0.000358 AC: 11 AN: 30720

American (AMR) AF: 0.0000955 AC: 1 AN: 10474

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.000280 AC: 1 AN: 3567

South Asian (SAS) AF: 0.00 AC: 0 AN: 2617

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5996

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 213

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53129

Other (OTH) AF: 0.00 AC: 0 AN: 1511

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000102

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.83
DANN	Benign	0.77
DEOGEN2	Benign	0.23	T
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.43	N
PhyloP100		0.47
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.16
Sift	Benign	0.085	T
Sift4G	Benign	0.23	T
Polyphen		0.0040	B
Vest4		0.017
MVP		0.38
MPC		0.76
ClinPred		0.024	T
GERP RS		-8.7
Varity_R		0.083
gMVP		0.53
Mutation Taster		=100/0	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; COSMIC: COSV53996724;