X-148500637-TGCCGCCGCC-T

Variant names:

• chrX-148500637-TGCCGCCGCC-T
• rs193922937
• NM_002025.4:c.-422_-414delCGCCGCCGC

Variant summary

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

The NM_002025.4(AFF2):​c.-422_-414delCGCCGCCGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 73,732 control chromosomes in the GnomAD database, including 10 homozygotes. There are 181 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.012 (10 hom., 180 hem., cov: 0)
  • Exomes 𝑓: 0.0033 (0 hom. 1 hem.)
• 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 = 0.0115 (841/73120) while in subpopulation NFE AF = 0.0139 (530/38013). AF 95% confidence interval is 0.013. There are 10 homozygotes in GnomAd4. There are 180 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFF2	NM_002025.4	c.-422_-414delCGCCGCCGC		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.-422_-414delCGCCGCCGC		5_prime_UTR_variant	Exon 1 of 21	5	NM_002025.4	ENSP00000359489.2
AFF2	ENST00000342251.7	c.-460_-452delGCCGCCGCC		upstream_gene_variant		1		ENSP00000345459.4
ENSG00000237741	ENST00000456981.1	n.-31_-23delGGCGGCGGC		upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 840 AN: 73135 Hom.: 10 Cov.: 0

Gnomad AFR AF: 0.00615

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0112

Gnomad ASJ AF: 0.00300

Gnomad EAS AF: 0.00599

Gnomad SAS AF: 0.0129

Gnomad FIN AF: 0.0318

Gnomad MID AF: 0.00980

Gnomad NFE AF: 0.0140

Gnomad OTH AF: 0.00741

GnomAD4 exome AF: 0.00327 AC: 2 AN: 612 Hom.: 0 AF XY: 0.00617 AC XY: 1 AN XY: 162

African (AFR) AF: 0.00 AC: 0 AN: 1

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.00186 AC: 1 AN: 539

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0169 AC: 1 AN: 59

Other (OTH) AF: 0.00 AC: 0 AN: 10

GnomAD4 genome AF: 0.0115 AC: 841 AN: 73120 Hom.: 10 Cov.: 0 AF XY: 0.0116 AC XY: 180 AN XY: 15464

African (AFR) AF: 0.00624 AC: 123 AN: 19701

American (AMR) AF: 0.0112 AC: 75 AN: 6671

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

East Asian (EAS) AF: 0.00602 AC: 12 AN: 1994

South Asian (SAS) AF: 0.0131 AC: 18 AN: 1373

European-Finnish (FIN) AF: 0.0318 AC: 61 AN: 1919

Middle Eastern (MID) AF: 0.0109 AC: 1 AN: 92

European-Non Finnish (NFE) AF: 0.0139 AC: 530 AN: 38013

Other (OTH) AF: 0.00735 AC: 7 AN: 952

Alfa AF: 0.00721 Hom.: 154

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.8
Mutation Taster		=299/1	polymorphism

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;