Genetic Variant AFF2:c.-443_-414dupCGCCGCCGCCGCCGCCGCCGCCGCCGCCGC (chrX-148500637-T-TGCCGCCGCCGCCGCCGCCGCCGCCGCCGCC) – 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.-443_-414dupCGCCGCCGCCGCCGCCGCCGCCGCCGCCGC 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 0.0096 ( 47 hom., 83 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 nfe. GnomAd4 allele frequency = 0.00964 (705/73108) while in subpopulation NFE AF = 0.0134 (510/38005). AF 95% confidence interval is 0.0125. There are 47 homozygotes in GnomAd4. There are 83 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 47 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFF2	NM_002025.4 link	c.-443_-414dupCGCCGCCGCCGCCGCCGCCGCCGCCGCCGC		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.-443_-414dupCGCCGCCGCCGCCGCCGCCGCCGCCGCCGC	5_prime_UTR_variant	Exon 1 of 21	5	NM_002025.4	ENSP00000359489.2	P51816-1
AFF2	ENST00000342251.7 link	c.-461_-460insGCCGCCGCCGCCGCCGCCGCCGCCGCCGCC	upstream_gene_variant		1		ENSP00000345459.4	P51816-3
ENSG00000237741	ENST00000456981.1 link	n.-52_-23dupGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC	upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00964

AC:

705

AN:

73123

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00686

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00435

Gnomad ASJ

AF:

0.0105

Gnomad EAS

AF:

0.000499

Gnomad SAS

AF:

0.00216

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00980

Gnomad NFE

AF:

0.0134

Gnomad OTH

AF:

0.00317

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00964

AC:

705

AN:

73108

Hom.:

Cov.:

AF XY:

0.00537

AC XY:

AN XY:

15468

show subpopulations

African (AFR)

AF:

0.00685

AC:

135

AN:

19695

American (AMR)

AF:

0.00435

AC:

AN:

6671

Ashkenazi Jewish (ASJ)

AF:

0.0105

AC:

AN:

1998

East Asian (EAS)

AF:

0.000502

AC:

AN:

1994

South Asian (SAS)

AF:

0.00218

AC:

AN:

1373

European-Finnish (FIN)

AF:

0.00104

AC:

AN:

1921

Middle Eastern (MID)

AF:

0.0109

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0134

AC:

510

AN:

38005

Other (OTH)

AF:

0.00315

AC:

AN:

953

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

115

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-TGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCC

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