rs864321652

Variant names:

• chrX-148995886-C-G
• rs864321652
• NM_002025.4:c.*4554C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002025.4(AFF2):​c.*4554C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: AFF2 NM_002025.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.425

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFF2	NM_002025.4	c.*4554C>G		3_prime_UTR_variant	Exon 21 of 21	ENST00000370460.7	NP_002016.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFF2	ENST00000370460.7	c.*4554C>G		3_prime_UTR_variant	Exon 21 of 21	5	NM_002025.4	ENSP00000359489.2
AFF2	ENST00000286437.7	c.*4554C>G		3_prime_UTR_variant	Exon 18 of 18	2		ENSP00000286437.5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 24

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

FRAXE Uncertain:1

-

Strand Center for Genomics and Personalized Medicine, Strand Life Sciences Pvt Ltd

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Though this variant has not been reported in a clinical context, 2 other variants in the 3'UTR of AFF2, *3206C>T and *2338T>C, have been reported in males with autism. The variants were shown to alter AFF2 gene expression levels in a tissue specific manner [PMID:22773736]. Both silencing and overexpression have been implicated in ASD susceptibility [PMID:22773736], [PMID:23562910]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	6.0
DANN	Benign	0.78

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs864321652; hg19: chrX-148077416;