X-148500637-TGCCGCCGCCGCCGCCGCCGCCGCCGCC-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_002025.4(AFF2):c.-440_-414del variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00089 (0 hom., 18 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: Uncertain significance criteria provided, single submitter U: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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000889 (65/73132) while in subpopulation AMR AF= 0.0042 (28/6671). AF 95% confidence interval is 0.00298. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Hemizygotes in GnomAd at 18 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AFF2	NM_002025.4	c.-440_-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.-440_-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: 0.000902 AC: 66 AN: 73147 Hom.: 0 Cov.: 0 AF XY: 0.00116 AC XY: 18 AN XY: 15461

Gnomad AFR AF: 0.000152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00420

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000499

Gnomad SAS AF: 0.000719

Gnomad FIN AF: 0.000521

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000841

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 614 Hom.: 0 AF XY: 0.00 AC XY: 0 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: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000889 AC: 65 AN: 73132 Hom.: 0 Cov.: 0 AF XY: 0.00116 AC XY: 18 AN XY: 15472

Gnomad4 AFR AF: 0.000152

Gnomad4 AMR AF: 0.00420

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000502

Gnomad4 SAS AF: 0.000728

Gnomad4 FIN AF: 0.000521

Gnomad4 NFE AF: 0.000815

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

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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;