rs5936428

Variant names:

• chrX-148771037-G-A
• rs5936428
• NM_002025.4:c.1042-38839G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002025.4(AFF2):​c.1042-38839G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0676 in 111,723 control chromosomes in the GnomAD database, including 267 homozygotes. There are 2,124 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.068 (267 hom., 2124 hem., cov: 23)
• Consequence: AFF2 NM_002025.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.19
• Publications: 1 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, G2P, Labcorp Genetics (formerly Invitae)
• 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 (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0972 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFF2	NM_002025.4	MANE Select	c.1042-38839G>A		intron	N/A	NP_002016.2
	AFF2	NM_001169123.2		c.1030-38839G>A		intron	N/A	NP_001162594.1
	AFF2	NM_001169122.2		c.1030-38839G>A		intron	N/A	NP_001162593.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFF2	ENST00000370460.7	TSL:5 MANE Select	c.1042-38839G>A		intron	N/A	ENSP00000359489.2
	AFF2	ENST00000342251.7	TSL:1	c.1030-38839G>A		intron	N/A	ENSP00000345459.4
	AFF2	ENST00000370457.9	TSL:1	c.1042-38839G>A		intron	N/A	ENSP00000359486.6

Frequencies

GnomAD3 genomes AF: 0.0676 AC: 7551 AN: 111671 Hom.: 267 Cov.: 23

Gnomad AFR AF: 0.0275

Gnomad AMI AF: 0.0919

Gnomad AMR AF: 0.0327

Gnomad ASJ AF: 0.0322

Gnomad EAS AF: 0.00309

Gnomad SAS AF: 0.0380

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.00840

Gnomad NFE AF: 0.0994

Gnomad OTH AF: 0.0543

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0676 AC: 7554 AN: 111723 Hom.: 267 Cov.: 23 AF XY: 0.0626 AC XY: 2124 AN XY: 33929

African (AFR) AF: 0.0276 AC: 851 AN: 30873

American (AMR) AF: 0.0326 AC: 344 AN: 10545

Ashkenazi Jewish (ASJ) AF: 0.0322 AC: 85 AN: 2640

East Asian (EAS) AF: 0.00310 AC: 11 AN: 3552

South Asian (SAS) AF: 0.0382 AC: 102 AN: 2673

European-Finnish (FIN) AF: 0.124 AC: 744 AN: 6007

Middle Eastern (MID) AF: 0.00922 AC: 2 AN: 217

European-Non Finnish (NFE) AF: 0.0994 AC: 5272 AN: 53031

Other (OTH) AF: 0.0536 AC: 81 AN: 1510

Alfa AF: 0.0900 Hom.: 527

Bravo AF: 0.0583

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.0
DANN	Benign	0.23
PhyloP100		1.2
Mutation Taster		=100/0	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: rs5936428; hg19: chrX-147852561;