chrX-148500637-T-TGCC

Variant names:

• chrX-148500637-T-TGCC
• rs193922937
• NM_002025.4:c.-416_-414dupCGC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_002025.4(AFF2):​c.-416_-414dupCGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.13 (678 hom., 1506 hem., cov: 0)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• 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.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFF2	NM_002025.4	c.-416_-414dupCGC		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.-416_-414dupCGC		5_prime_UTR_variant	Exon 1 of 21	5	NM_002025.4	ENSP00000359489.2
AFF2	ENST00000342251.7	c.-461_-460insGCC		upstream_gene_variant		1		ENSP00000345459.4
ENSG00000237741	ENST00000456981.1	n.-25_-23dupGGC		upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.126 AC: 9217 AN: 73091 Hom.: 676 Cov.: 0

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.0788

Gnomad AMR AF: 0.0958

Gnomad ASJ AF: 0.0925

Gnomad EAS AF: 0.0624

Gnomad SAS AF: 0.0712

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.109

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 613 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 163

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: 0.00 AC: 0 AN: 539

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

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 60

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

GnomAD4 genome AF: 0.126 AC: 9218 AN: 73076 Hom.: 678 Cov.: 0 AF XY: 0.0974 AC XY: 1506 AN XY: 15456

African (AFR) AF: 0.141 AC: 2770 AN: 19691

American (AMR) AF: 0.0958 AC: 639 AN: 6670

Ashkenazi Jewish (ASJ) AF: 0.0925 AC: 185 AN: 1999

East Asian (EAS) AF: 0.0622 AC: 124 AN: 1992

South Asian (SAS) AF: 0.0699 AC: 96 AN: 1373

European-Finnish (FIN) AF: 0.116 AC: 222 AN: 1919

Middle Eastern (MID) AF: 0.130 AC: 12 AN: 92

European-Non Finnish (NFE) AF: 0.132 AC: 5029 AN: 37986

Other (OTH) AF: 0.115 AC: 109 AN: 948

Alfa AF: 0.0227 Hom.: 154

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;