rs12011040

Variant names:

• chrX-148953670-G-A
• rs12011040
• NM_002025.4:c.1488G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-148953670-G-A
• chrX-148953670-G-C
• chrX-148953670-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002025.4(AFF2):​c.1488G>A​(p.Ser496Ser) 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:6
• Conservation: PhyloP100: -7.97
• Publications: 7 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 -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 VariationId is 128281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.1488G>A	p.Ser496Ser	synonymous	Exon 10 of 21	NP_002016.2	P51816-1
	AFF2	NM_001169123.2		c.1458G>A	p.Ser486Ser	synonymous	Exon 10 of 21	NP_001162594.1	P51816-5
	AFF2	NM_001169122.2		c.1389G>A	p.Ser463Ser	synonymous	Exon 9 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.1488G>A	p.Ser496Ser	synonymous	Exon 10 of 21	ENSP00000359489.2	P51816-1
	AFF2	ENST00000342251.7	TSL:1	c.1389G>A	p.Ser463Ser	synonymous	Exon 9 of 20	ENSP00000345459.4	P51816-3
	AFF2	ENST00000370457.9	TSL:1	c.1383G>A	p.Ser461Ser	synonymous	Exon 9 of 20	ENSP00000359486.6	P51816-6

Frequencies

GnomAD3 genomes AF: 0.140 AC: 15462 AN: 110754 Hom.: 1778 Cov.: 22

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

GnomAD2 exomes AF: 0.0649 AC: 11878 AN: 182894 AF XY: 0.0556

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 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

African (AFR) AF: 0.416 AC: 10978 AN: 26387

American (AMR) AF: 0.0326 AC: 1149 AN: 35192

Ashkenazi Jewish (ASJ) AF: 0.0741 AC: 1435 AN: 19374

East Asian (EAS) AF: 0.00113 AC: 34 AN: 30198

South Asian (SAS) AF: 0.0336 AC: 1816 AN: 54098

European-Finnish (FIN) AF: 0.0629 AC: 2550 AN: 40522

Middle Eastern (MID) AF: 0.0656 AC: 271 AN: 4134

European-Non Finnish (NFE) AF: 0.0365 AC: 30711 AN: 841728

Other (OTH) AF: 0.0621 AC: 2860 AN: 46074

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

African (AFR) AF: 0.385 AC: 11596 AN: 30137

American (AMR) AF: 0.0665 AC: 698 AN: 10504

Ashkenazi Jewish (ASJ) AF: 0.0813 AC: 215 AN: 2646

East Asian (EAS) AF: 0.00284 AC: 10 AN: 3522

South Asian (SAS) AF: 0.0245 AC: 64 AN: 2613

European-Finnish (FIN) AF: 0.0587 AC: 349 AN: 5944

Middle Eastern (MID) AF: 0.0837 AC: 18 AN: 215

European-Non Finnish (NFE) AF: 0.0419 AC: 2223 AN: 53035

Other (OTH) AF: 0.107 AC: 162 AN: 1517

Alfa AF: 0.0835 Hom.: 3619

Bravo AF: 0.156

EpiCase AF: 0.0398

EpiControl AF: 0.0405

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	FRAXE (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.12
DANN	Benign	0.61
PhyloP100		-8.0
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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