X-148500637-TGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCC-TGCCGCCGCCGCCGCCGCC

Variant names:

• chrX-148500637-TGCCGCCGCCGCCGCCGCCGCCGCC-T
• rs193922937
• NM_002025.4:c.-437_-414delCGCCGCCGCCGCCGCCGCCGCCGC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_002025.4(AFF2):​c.-437_-414delCGCCGCCGCCGCCGCCGCCGCCGC 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 DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., 20 hem., cov: 0)
  • Exomes 𝑓: 0.0016 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: AFF2 NM_002025.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant X-148500637-TGCCGCCGCCGCCGCCGCCGCCGCC-T is Benign according to our data. Variant chrX-148500637-TGCCGCCGCCGCCGCCGCCGCCGCC-T is described in ClinVar as [Likely_benign]. Clinvar id is 2661597.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00123 (90/73131) while in subpopulation AMR AF = 0.00405 (27/6668). AF 95% confidence interval is 0.00286. There are 0 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 20 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFF2	NM_002025.4	c.-437_-414delCGCCGCCGCCGCCGCCGCCGCCGC		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.-437_-414delCGCCGCCGCCGCCGCCGCCGCCGC		5_prime_UTR_variant	Exon 1 of 21	5	NM_002025.4	ENSP00000359489.2
AFF2	ENST00000342251.7	c.-460_-437delGCCGCCGCCGCCGCCGCCGCCGCC		upstream_gene_variant		1		ENSP00000345459.4
ENSG00000237741	ENST00000456981.1	n.-46_-23delGGCGGCGGCGGCGGCGGCGGCGGC		upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 89 AN: 73146 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000864

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00405

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000499

Gnomad SAS AF: 0.000719

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000973

Gnomad OTH AF: 0.00423

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00163 AC: 1 AN: 614 Hom.: 0 AF XY: 0.00610 AC XY: 1 AN XY: 164

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: 0.00185 AC: 1 AN: 540

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: 0.00123 AC: 90 AN: 73131 Hom.: 0 Cov.: 0 AF XY: 0.00129 AC XY: 20 AN XY: 15473

African (AFR) AF: 0.000913 AC: 18 AN: 19705

American (AMR) AF: 0.00405 AC: 27 AN: 6668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1999

East Asian (EAS) AF: 0.000502 AC: 1 AN: 1994

South Asian (SAS) AF: 0.000728 AC: 1 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: 0.000973 AC: 37 AN: 38020

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

Alfa AF: 0.00 Hom.: 154

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

AFF2: BS2 -

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;