chrX-148500637-T-TGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCC

Variant names:

• chrX-148500637-T-TGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCC
• rs193922937
• NM_002025.4:c.-449_-414dupCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_002025.4(AFF2):​c.-449_-414dupCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0028 (12 hom., 16 hem., cov: 0)
• Consequence: AFF2 NM_002025.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.80
• 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

ENSG00000237741 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00284 (208/73128) while in subpopulation NFE AF = 0.00342 (130/38022). AF 95% confidence interval is 0.00294. There are 12 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFF2	NM_002025.4	c.-449_-414dupCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGC		5_prime_UTR_variant	Exon 1 of 21	ENST00000370460.7	NP_002016.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFF2	ENST00000370460.7	c.-449_-414dupCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGC		5_prime_UTR_variant	Exon 1 of 21	5	NM_002025.4	ENSP00000359489.2
AFF2	ENST00000342251.7	c.-461_-460insGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCC		upstream_gene_variant		1		ENSP00000345459.4
ENSG00000237741	ENST00000456981.1	n.-58_-23dupGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC		upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00284 AC: 208 AN: 73143 Hom.: 12 Cov.: 0

Gnomad AFR AF: 0.00254

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.00300

Gnomad EAS AF: 0.00200

Gnomad SAS AF: 0.00144

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00342

Gnomad OTH AF: 0.00423

GnomAD4 exome Cov.: 0

GnomAD4 genome AF: 0.00284 AC: 208 AN: 73128 Hom.: 12 Cov.: 0 AF XY: 0.00103 AC XY: 16 AN XY: 15474

African (AFR) AF: 0.00254 AC: 50 AN: 19699

American (AMR) AF: 0.00150 AC: 10 AN: 6669

Ashkenazi Jewish (ASJ) AF: 0.00300 AC: 6 AN: 1999

East Asian (EAS) AF: 0.00201 AC: 4 AN: 1994

South Asian (SAS) AF: 0.00146 AC: 2 AN: 1373

European-Finnish (FIN) AF: 0.00104 AC: 2 AN: 1921

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 92

European-Non Finnish (NFE) AF: 0.00342 AC: 130 AN: 38022

Other (OTH) AF: 0.00420 AC: 4 AN: 953

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.8

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs193922937; hg19: chrX-147582157;