Genetic Variant AFF2:c.-425_-414dupCGCCGCCGCCGC (chrX-148500637-T-TGCCGCCGCCGCC) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_002025.4(AFF2):c.-425_-414dupCGCCGCCGCCGC 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 0.048 ( 225 hom., 487 hem., cov: 0)

Exomes 𝑓: 0.0016 ( 0 hom. 1 hem. )

Failed GnomAD Quality Control

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0829 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFF2	NM_002025.4 link	c.-425_-414dupCGCCGCCGCCGC		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.-425_-414dupCGCCGCCGCCGC	5_prime_UTR_variant	Exon 1 of 21	5	NM_002025.4	ENSP00000359489.2	P51816-1
AFF2	ENST00000342251.7 link	c.-461_-460insGCCGCCGCCGCC	upstream_gene_variant		1		ENSP00000345459.4	P51816-3
ENSG00000237741	ENST00000456981.1 link	n.-34_-23dupGGCGGCGGCGGC	upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0477

AC:

3484

AN:

73110

Hom.:

224

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0223

Gnomad AMI

AF:

0.0690

Gnomad AMR

AF:

0.0804

Gnomad ASJ

AF:

0.0536

Gnomad EAS

AF:

0.0944

Gnomad SAS

AF:

0.0489

Gnomad FIN

AF:

0.0344

Gnomad MID

AF:

0.0490

Gnomad NFE

AF:

0.0526

Gnomad OTH

AF:

0.0508

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00163

AC:

AN:

614

Hom.:

Cov.:

AF XY:

0.00610

AC XY:

AN XY:

164

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

540

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0167

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

GnomAD4 genome

AF:

0.0477

AC:

3483

AN:

73095

Hom.:

225

Cov.:

AF XY:

0.0315

AC XY:

487

AN XY:

15457

show subpopulations

African (AFR)

AF:

0.0224

AC:

441

AN:

19697

American (AMR)

AF:

0.0807

AC:

538

AN:

6668

Ashkenazi Jewish (ASJ)

AF:

0.0536

AC:

107

AN:

1998

East Asian (EAS)

AF:

0.0939

AC:

187

AN:

1991

South Asian (SAS)

AF:

0.0473

AC:

AN:

1373

European-Finnish (FIN)

AF:

0.0344

AC:

AN:

1920

Middle Eastern (MID)

AF:

0.0543

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0526

AC:

1998

AN:

37998

Other (OTH)

AF:

0.0504

AC:

AN:

952

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

119

238

356

475

594

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0109

Hom.:

154

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-TGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over