X-148500637-TGCCGCCGCCGCCGCCGCCGCCGCC-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_002025.4(AFF2):c.-437_-414del variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. 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

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 20 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AFF2	NM_002025.4	c.-437_-414del		5_prime_UTR_variant	1/21	ENST00000370460.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AFF2	ENST00000370460.7	c.-437_-414del		5_prime_UTR_variant	1/21	5	NM_002025.4	P1
AFF2	ENST00000342251.7			upstream_gene_variant		1
	ENST00000456981.1			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 89 AN: 73146 Hom.: 0 Cov.: 0 AF XY: 0.00129 AC XY: 20 AN XY: 15462

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 SAS exome AF: 0.00185

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00123 AC: 90 AN: 73131 Hom.: 0 Cov.: 0 AF XY: 0.00129 AC XY: 20 AN XY: 15473

Gnomad4 AFR AF: 0.000913

Gnomad4 AMR AF: 0.00405

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000502

Gnomad4 SAS AF: 0.000728

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.000973

Gnomad4 OTH AF: 0.00420

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

AFF2: BS2 -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs193922937; hg19: chrX-147582157;