rs201152809

Positions:

• chrX-148662288-C-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_002025.4(AFF2):​c.561C>A​(p.Asp187Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,210,003 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 17 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000054 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.000041 (0 hom. 15 hem.)
• Consequence: AFF2 NM_002025.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.121

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09731996).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000537 (6/111770) while in subpopulation NFE AF= 0.000113 (6/53184). AF 95% confidence interval is 0.0000484. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AFF2	NM_002025.4	c.561C>A	p.Asp187Glu	missense_variant	3/21	ENST00000370460.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AFF2	ENST00000370460.7	c.561C>A	p.Asp187Glu	missense_variant	3/21	5	NM_002025.4	P1
AFF2	ENST00000342251.7	c.549C>A	p.Asp183Glu	missense_variant	3/20	1
AFF2	ENST00000370457.9	c.561C>A	p.Asp187Glu	missense_variant	3/20	1
AFF2	ENST00000370458.5	c.549C>A	p.Asp183Glu	missense_variant	3/8	1

Frequencies

GnomAD3 genomes AF: 0.0000537 AC: 6 AN: 111770 Hom.: 0 Cov.: 23 AF XY: 0.0000589 AC XY: 2 AN XY: 33950

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: 0.000113

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000273 AC: 5 AN: 183428 Hom.: 0 AF XY: 0.0000295 AC XY: 2 AN XY: 67872

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000488

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000410 AC: 45 AN: 1098233 Hom.: 0 Cov.: 32 AF XY: 0.0000413 AC XY: 15 AN XY: 363587

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000499

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome AF: 0.0000537 AC: 6 AN: 111770 Hom.: 0 Cov.: 23 AF XY: 0.0000589 AC XY: 2 AN XY: 33950

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000113

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000170 Hom.: 1

Bravo AF: 0.0000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000297 AC: 2

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

Oct 10, 2016

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2022

The c.561C>A (p.D187E) alteration is located in exon 3 (coding exon 3) of the AFF2 gene. This alteration results from a C to A substitution at nucleotide position 561, causing the aspartic acid (D) at amino acid position 187 to be replaced by a glutamic acid (E). 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	0.083
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T;.;.;.
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.71	T;T;T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.097	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;.;.;L
MutationTaster	Benign	0.74	N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.1	N;N;N;.
REVEL	Benign	0.054
Sift	Benign	0.058	T;T;T;.
Sift4G	Benign	0.31	T;T;T;T
Polyphen		0.77	P;P;P;P
Vest4		0.12
MutPred		0.32		Gain of methylation at K192 (P = 0.1338);.;.;Gain of methylation at K192 (P = 0.1338);
MVP		0.58
MPC		0.13
ClinPred		0.083	T
GERP RS		1.6
Varity_R		0.14
gMVP		0.14

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

Publications

LitVar

Other links and lift over

dbSNP: rs201152809; hg19: chrX-147743809;