Genetic Variant AFF2:c.-419_-414delCGCCGC (chrX-148500637-TGCCGCC-T) – 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.-419_-414delCGCCGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 73,737 control chromosomes in the GnomAD database, including 6 homozygotes. There are 126 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.011 ( 6 hom., 125 hem., cov: 0)

Exomes 𝑓: 0.0016 ( 0 hom. 1 hem. )

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 eas. GnomAd4 allele frequency = 0.0111 (815/73125) while in subpopulation EAS AF = 0.0171 (34/1993). AF 95% confidence interval is 0.0128. There are 6 homozygotes in GnomAd4. There are 125 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002025.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
AFF2	NM_002025.4	MANE Select	c.-419_-414delCGCCGC	5_prime_UTR	Exon 1 of 21	NP_002016.2
AFF2	NM_001169123.2		c.-419_-414delCGCCGC	5_prime_UTR	Exon 1 of 21	NP_001162594.1
AFF2	NM_001169122.2		c.-419_-414delCGCCGC	5_prime_UTR	Exon 1 of 20	NP_001162593.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
AFF2	ENST00000370460.7	TSL:5 MANE Select	c.-419_-414delCGCCGC	5_prime_UTR	Exon 1 of 21	ENSP00000359489.2
AFF2	ENST00000342251.7	TSL:1	c.-460_-455delGCCGCC	upstream_gene	N/A	ENSP00000345459.4
ENSG00000237741	ENST00000456981.1	TSL:3	n.-28_-23delGGCGGC	upstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.0112

AC:

816

AN:

73140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0142

Gnomad AMI

AF:

0.0123

Gnomad AMR

AF:

0.00705

Gnomad ASJ

AF:

0.00300

Gnomad EAS

AF:

0.0170

Gnomad SAS

AF:

0.0165

Gnomad FIN

AF:

0.00312

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0107

Gnomad OTH

AF:

0.00951

GnomAD4 exome

AF:

0.00163

AC:

AN:

612

Hom.:

AF XY:

0.00617

AC XY:

AN XY:

162

show subpopulations

African (AFR)

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:

0.00185

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:

0.0111

AC:

815

AN:

73125

Hom.:

Cov.:

AF XY:

0.00808

AC XY:

125

AN XY:

15469

show subpopulations

African (AFR)

AF:

0.0142

AC:

279

AN:

19702

American (AMR)

AF:

0.00705

AC:

AN:

6671

Ashkenazi Jewish (ASJ)

AF:

0.00300

AC:

AN:

1999

East Asian (EAS)

AF:

0.0171

AC:

AN:

1993

South Asian (SAS)

AF:

0.0168

AC:

AN:

1373

European-Finnish (FIN)

AF:

0.00312

AC:

AN:

1921

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0107

AC:

406

AN:

38016

Other (OTH)

AF:

0.00944

AC:

AN:

953

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

118

148

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

154

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over