Genetic Variant NM_002025.4:c.-416_-414delCGC (chrX-148500637-TGCC-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.-416_-414delCGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.024 ( 30 hom., 282 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

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 = 0.0242 (1773/73119) while in subpopulation EAS AF = 0.0281 (56/1993). AF 95% confidence interval is 0.0263. There are 30 homozygotes in GnomAd4. There are 282 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 30 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFF2	NM_002025.4 link	c.-416_-414delCGC		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.-416_-414delCGC	5_prime_UTR_variant	Exon 1 of 21	5	NM_002025.4	ENSP00000359489.2	P51816-1
AFF2	ENST00000342251.7 link	c.-460_-458delGCC	upstream_gene_variant		1		ENSP00000345459.4	P51816-3
ENSG00000237741	ENST00000456981.1 link	n.-25_-23delGGC	upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0243

AC:

1775

AN:

73134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0205

Gnomad AMI

AF:

0.00246

Gnomad AMR

AF:

0.0231

Gnomad ASJ

AF:

0.0190

Gnomad EAS

AF:

0.0279

Gnomad SAS

AF:

0.0137

Gnomad FIN

AF:

0.0135

Gnomad MID

AF:

0.0294

Gnomad NFE

AF:

0.0277

Gnomad OTH

AF:

0.0233

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

610

Hom.:

AF XY:

0.00

AC XY:

AN XY:

162

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:

538

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:

0.0242

AC:

1773

AN:

73119

Hom.:

Cov.:

AF XY:

0.0182

AC XY:

282

AN XY:

15473

show subpopulations

African (AFR)

AF:

0.0205

AC:

404

AN:

19701

American (AMR)

AF:

0.0231

AC:

154

AN:

6669

Ashkenazi Jewish (ASJ)

AF:

0.0190

AC:

AN:

1997

East Asian (EAS)

AF:

0.0281

AC:

AN:

1993

South Asian (SAS)

AF:

0.0117

AC:

AN:

1373

European-Finnish (FIN)

AF:

0.0135

AC:

AN:

1921

Middle Eastern (MID)

AF:

0.0326

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0277

AC:

1053

AN:

38014

Other (OTH)

AF:

0.0231

AC:

AN:

953

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

131

196

262

327

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

154

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.8

Mutation Taster

=299/1

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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NM_002025.4:c.-416_-414delCGC

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