chrX-148500637-TGCCGCC-T

Variant names:

• chrX-148500637-TGCCGCC-T
• rs193922937
• NM_002025.4:c.-419_-414delCGCCGC

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.80

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]

ENSG00000237741 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFF2	NM_002025.4	c.-419_-414delCGCCGC		5_prime_UTR_variant	Exon 1 of 21	ENST00000370460.7	NP_002016.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFF2	ENST00000370460	c.-419_-414delCGCCGC		5_prime_UTR_variant	Exon 1 of 21	5	NM_002025.4	ENSP00000359489.2
AFF2	ENST00000342251.7	c.-460_-455delGCCGCC		upstream_gene_variant		1		ENSP00000345459.4
ENSG00000237741	ENST00000456981.1	n.-28_-23delGGCGGC		upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 816 AN: 73140 Hom.: 6 Cov.: 0 AF XY: 0.00815 AC XY: 126 AN XY: 15458

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: 1 AN: 612 Hom.: 0 AF XY: 0.00617 AC XY: 1 AN XY: 162

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 SAS exome AF: 0.00185

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0111 AC: 815 AN: 73125 Hom.: 6 Cov.: 0 AF XY: 0.00808 AC XY: 125 AN XY: 15469

Gnomad4 AFR AF: 0.0142

Gnomad4 AMR AF: 0.00705

Gnomad4 ASJ AF: 0.00300

Gnomad4 EAS AF: 0.0171

Gnomad4 SAS AF: 0.0168

Gnomad4 FIN AF: 0.00312

Gnomad4 NFE AF: 0.0107

Gnomad4 OTH AF: 0.00944

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs193922937; hg19: chrX-147582157;