Genetic Variant AFF2:c.-440_-414delCGCCGCCGCCGCCGCCGCCGCCGCCGC (chrX-148500637-TGCCGCCGCCGCCGCCGCCGCCGCCGCC-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_002025.4(AFF2):c.-440_-414delCGCCGCCGCCGCCGCCGCCGCCGCCGC 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 DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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: Likely_benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Hemizygotes in GnomAd4 at 18 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFF2	NM_002025.4 link	c.-440_-414delCGCCGCCGCCGCCGCCGCCGCCGCCGC		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.-440_-414delCGCCGCCGCCGCCGCCGCCGCCGCCGC	5_prime_UTR_variant	Exon 1 of 21	5	NM_002025.4	ENSP00000359489.2	P51816-1
AFF2	ENST00000342251.7 link	c.-460_-434delGCCGCCGCCGCCGCCGCCGCCGCCGCC	upstream_gene_variant		1		ENSP00000345459.4	P51816-3
ENSG00000237741	ENST00000456981.1 link	n.-49_-23delGGCGGCGGCGGCGGCGGCGGCGGCGGC	upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000902

AC:

AN:

73147

Hom.:

Cov.:

show subpopulations

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:

AN:

614

Hom.:

AF XY:

0.00

AC XY:

AN XY:

164

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:

0.00

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

GnomAD4 genome

AF:

0.000889

AC:

AN:

73132

Hom.:

Cov.:

AF XY:

0.00116

AC XY:

AN XY:

15472

show subpopulations

African (AFR)

AF:

0.000152

AC:

AN:

19705

American (AMR)

AF:

0.00420

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:

0.000728

AC:

AN:

1373

European-Finnish (FIN)

AF:

0.000521

AC:

AN:

1921

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000815

AC:

AN:

38018

Other (OTH)

AF:

0.00

AC:

AN:

953

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.569

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

154

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 04, 2022

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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-TGCCGCCGCCGCCGCC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over