Genetic Variant AFF2:c.-458_-414dupCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGC (chrX-148500637-T-TGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCC) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_002025.4(AFF2):c.-458_-414dupCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGC 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 INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00060 ( 0 hom., 5 hem., cov: 0)

Consequence

AFF2
NM_002025.4 5_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.80

Publications

1 publications found

Variant links:

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

AFF2 links:

ENSG00000237741 (HGNC:):

ENSG00000237741 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000602 (44/73132) while in subpopulation AFR AF = 0.000863 (17/19703). AF 95% confidence interval is 0.000549. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFF2	NM_002025.4 link	c.-458_-414dupCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGC		5_prime_UTR_variant	Exon 1 of 21	ENST00000370460.7	NP_002016.2	P51816-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
AFF2	ENST00000370460.7 link	c.-458_-414dupCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGC	5_prime_UTR_variant	Exon 1 of 21	5	NM_002025.4	ENSP00000359489.2	P51816-1
AFF2	ENST00000342251.7 link	c.-461_-460insGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCC	upstream_gene_variant		1		ENSP00000345459.4	P51816-3
ENSG00000237741	ENST00000456981.1 link	n.-67_-23dupGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC	upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000602

AC:

AN:

73147

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000864

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000750

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000499

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000526

Gnomad OTH

AF:

0.00106

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.000602

AC:

AN:

73132

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

15474

show subpopulations

African (AFR)

AF:

0.000863

AC:

AN:

19703

American (AMR)

AF:

0.000750

AC:

AN:

6671

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1999

East Asian (EAS)

AF:

0.000502

AC:

AN:

1994

South Asian (SAS)

AF:

0.00

AC:

AN:

1373

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1921

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000526

AC:

AN:

38020

Other (OTH)

AF:

0.00105

AC:

AN:

953

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Publications

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X-148500637-TGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCC-TGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over