rs12011040

chrX-148953670-G-AchrX-148953670-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002025.4(AFF2):c.1488G>A(p.Ser496=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0557 in 1,208,514 control chromosomes in the GnomAD database, including 4,114 homozygotes. There are 20,624 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1779 hom., 4175 hem., cov: 22)
  • Exomes 𝑓: 0.047 (2335 hom. 16449 hem.)
• Consequence: AFF2 NM_002025.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -7.97

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP6: Variant X-148953670-G-A is Benign according to our data. Variant chrX-148953670-G-A is described in ClinVar as [Benign]. Clinvar id is 128281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-148953670-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-7.97 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.379 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AFF2	NM_002025.4	c.1488G>A	p.Ser496=	synonymous_variant	10/21	ENST00000370460.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AFF2	ENST00000370460.7	c.1488G>A	p.Ser496=	synonymous_variant	10/21	5	NM_002025.4	P1

Frequencies

GnomAD3 genomes AF: 0.140 AC: 15462 AN: 110754 Hom.: 1778 Cov.: 22 AF XY: 0.126 AC XY: 4159 AN XY: 33010

Gnomad AFR AF: 0.385

Gnomad AMI AF: 0.228

Gnomad AMR AF: 0.0667

Gnomad ASJ AF: 0.0813

Gnomad EAS AF: 0.00283

Gnomad SAS AF: 0.0244

Gnomad FIN AF: 0.0587

Gnomad MID AF: 0.0805

Gnomad NFE AF: 0.0419

Gnomad OTH AF: 0.106

GnomAD3 exomes AF: 0.0649 AC: 11878 AN: 182894 Hom.: 946 AF XY: 0.0556 AC XY: 3750 AN XY: 67416

Gnomad AFR exome AF: 0.405

Gnomad AMR exome AF: 0.0287

Gnomad ASJ exome AF: 0.0735

Gnomad EAS exome AF: 0.00209

Gnomad SAS exome AF: 0.0336

Gnomad FIN exome AF: 0.0617

Gnomad NFE exome AF: 0.0411

Gnomad OTH exome AF: 0.0480

GnomAD4 exome AF: 0.0472 AC: 51804 AN: 1097707 Hom.: 2335 Cov.: 30 AF XY: 0.0453 AC XY: 16449 AN XY: 363105

Gnomad4 AFR exome AF: 0.416

Gnomad4 AMR exome AF: 0.0326

Gnomad4 ASJ exome AF: 0.0741

Gnomad4 EAS exome AF: 0.00113

Gnomad4 SAS exome AF: 0.0336

Gnomad4 FIN exome AF: 0.0629

Gnomad4 NFE exome AF: 0.0365

Gnomad4 OTH exome AF: 0.0621

GnomAD4 genome AF: 0.140 AC: 15489 AN: 110807 Hom.: 1779 Cov.: 22 AF XY: 0.126 AC XY: 4175 AN XY: 33073

Gnomad4 AFR AF: 0.385

Gnomad4 AMR AF: 0.0665

Gnomad4 ASJ AF: 0.0813

Gnomad4 EAS AF: 0.00284

Gnomad4 SAS AF: 0.0245

Gnomad4 FIN AF: 0.0587

Gnomad4 NFE AF: 0.0419

Gnomad4 OTH AF: 0.107

Alfa AF: 0.0711 Hom.: 2113

Bravo AF: 0.156

EpiCase AF: 0.0398

EpiControl AF: 0.0405

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 21, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 17, 2013	- -

FRAXE Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
Cadd	Benign	0.12
Dann	Benign	0.61

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: rs12011040; hg19: chrX-148035200; COSMIC: COSV54012793;