rs985595

Variant names:

• chrX-148640445-C-G
• rs985595
• NM_002025.4:c.48-11554C>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_002025.4(AFF2):​c.48-11554C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 109,168 control chromosomes in the GnomAD database, including 1,416 homozygotes. There are 5,549 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 0.18 (1416 hom., 5549 hem., cov: 22)
• Consequence: AFF2 NM_002025.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.10
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.193 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFF2	NM_002025.4	c.48-11554C>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.48-11554C>G		intron_variant	Intron 1 of 20	5	NM_002025.4	ENSP00000359489.2
AFF2	ENST00000342251.7	c.48-11554C>G		intron_variant	Intron 1 of 19	1		ENSP00000345459.4
AFF2	ENST00000370457.9	c.48-11554C>G		intron_variant	Intron 1 of 19	1		ENSP00000359486.6
AFF2	ENST00000370458.5	c.48-11554C>G		intron_variant	Intron 1 of 7	1		ENSP00000359487.1

Frequencies

GnomAD3 genomes AF: 0.185 AC: 20182 AN: 109109 Hom.: 1413 Cov.: 22

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.183

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.176

Gnomad EAS AF: 0.00588

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.263

Gnomad MID AF: 0.143

Gnomad NFE AF: 0.197

Gnomad OTH AF: 0.192

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

GnomAD4 genome AF: 0.185 AC: 20186 AN: 109168 Hom.: 1416 Cov.: 22 AF XY: 0.175 AC XY: 5549 AN XY: 31744

African (AFR) AF: 0.184 AC: 5566 AN: 30174

American (AMR) AF: 0.154 AC: 1588 AN: 10298

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 461 AN: 2618

East Asian (EAS) AF: 0.00589 AC: 20 AN: 3393

South Asian (SAS) AF: 0.152 AC: 375 AN: 2470

European-Finnish (FIN) AF: 0.263 AC: 1439 AN: 5467

Middle Eastern (MID) AF: 0.148 AC: 32 AN: 216

European-Non Finnish (NFE) AF: 0.197 AC: 10296 AN: 52376

Other (OTH) AF: 0.193 AC: 288 AN: 1495

Alfa AF: 0.197 Hom.: 1158

Bravo AF: 0.182

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	20
DANN	Benign	0.67
PhyloP100		3.1
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: rs985595; hg19: chrX-147721966;