rs373659849

chrX-148980756-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting 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. 15/20 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

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]

ACMG classification

Verdict is Benign. Variant got -9 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 male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Hemizygotes in GnomAd at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AFF2	NM_002025.4	c.3589G>A	p.Ala1197Thr	missense_variant	19/21	ENST00000370460.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AFF2	ENST00000370460.7	c.3589G>A	p.Ala1197Thr	missense_variant	19/21	5	NM_002025.4	P1

Frequencies

GnomAD3 genomes AF: 0.000117 AC: 13 AN: 111496 Hom.: 0 Cov.: 23 AF XY: 0.000207 AC XY: 7 AN XY: 33772

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

GnomAD3 exomes AF: 0.0000384 AC: 7 AN: 182519 Hom.: 0 AF XY: 0.0000597 AC XY: 4 AN XY: 67017

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 SAS exome AF: 0.000106

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

Gnomad4 AFR exome AF: 0.000115

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000114

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000601

Gnomad4 OTH exome AF: 0.0000221

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

Gnomad4 AFR AF: 0.000358

Gnomad4 AMR AF: 0.0000955

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000280

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000102

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 11, 2016

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 23, 2023

The c.3589G>A (p.A1197T) alteration is located in exon 19 (coding exon 19) of the AFF2 gene. This alteration results from a G to A substitution at nucleotide position 3589, causing the alanine (A) at amino acid position 1197 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;T;T;T
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.033	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.43	N;.;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.8	N;.;N;N
REVEL	Benign	0.16
Sift	Benign	0.085	T;.;T;T
Sift4G	Benign	0.23	T;T;T;T
Polyphen		0.0040	B;B;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs373659849; hg19: chrX-148062286; COSMIC: COSV53996724;