NM_002025.4:c.48-50168C>G

Variant names:

• chrX-148601831-C-G
• rs5980376
• NM_002025.4:c.48-50168C>G

Variant summary

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

The NM_002025.4(AFF2):​c.48-50168C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0485 in 111,697 control chromosomes in the GnomAD database, including 316 homozygotes. There are 1,480 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 0.049 (316 hom., 1480 hem., cov: 23)
• Consequence: AFF2 NM_002025.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.779
• Publications: 0 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFF2	NM_002025.4	c.48-50168C>G		intron_variant	Intron 1 of 20	ENST00000370460.7	NP_002016.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFF2	ENST00000370460.7	c.48-50168C>G		intron_variant	Intron 1 of 20	5	NM_002025.4	ENSP00000359489.2
AFF2	ENST00000342251.7	c.48-50168C>G		intron_variant	Intron 1 of 19	1		ENSP00000345459.4
AFF2	ENST00000370457.9	c.48-50168C>G		intron_variant	Intron 1 of 19	1		ENSP00000359486.6
AFF2	ENST00000370458.5	c.48-50168C>G		intron_variant	Intron 1 of 7	1		ENSP00000359487.1

Frequencies

GnomAD3 genomes AF: 0.0485 AC: 5420 AN: 111647 Hom.: 316 Cov.: 23

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0163

Gnomad ASJ AF: 0.00377

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000747

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0169

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.0320

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

GnomAD4 genome AF: 0.0485 AC: 5422 AN: 111697 Hom.: 316 Cov.: 23 AF XY: 0.0436 AC XY: 1480 AN XY: 33941

African (AFR) AF: 0.167 AC: 5135 AN: 30661

American (AMR) AF: 0.0164 AC: 173 AN: 10575

Ashkenazi Jewish (ASJ) AF: 0.00377 AC: 10 AN: 2655

East Asian (EAS) AF: 0.00 AC: 0 AN: 3547

South Asian (SAS) AF: 0.000749 AC: 2 AN: 2669

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6029

Middle Eastern (MID) AF: 0.0186 AC: 4 AN: 215

European-Non Finnish (NFE) AF: 0.000941 AC: 50 AN: 53139

Other (OTH) AF: 0.0316 AC: 48 AN: 1517

Alfa AF: 0.00882 Hom.: 25

Bravo AF: 0.0566

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.37
DANN	Benign	0.39
PhyloP100		-0.78
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: rs5980376; hg19: chrX-147683352;