X-148662021-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002025.4(AFF2):c.294A>G(p.Pro98=) variant causes a synonymous change. The variant allele was found at a frequency of 0.000383 in 1,209,078 control chromosomes in the GnomAD database, including 1 homozygotes. There are 138 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., 3 hem., cov: 23)
  • Exomes 𝑓: 0.00040 (1 hom. 135 hem.)
• Consequence: AFF2 NM_002025.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.64

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant X-148662021-A-G is Benign according to our data. Variant chrX-148662021-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 728558.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000232 (26/111898) while in subpopulation NFE AF= 0.000432 (23/53190). AF 95% confidence interval is 0.000295. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AFF2	NM_002025.4	c.294A>G	p.Pro98=	synonymous_variant	3/21	ENST00000370460.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AFF2	ENST00000370460.7	c.294A>G	p.Pro98=	synonymous_variant	3/21	5	NM_002025.4	P1
AFF2	ENST00000342251.7	c.282A>G	p.Pro94=	synonymous_variant	3/20	1
AFF2	ENST00000370457.9	c.294A>G	p.Pro98=	synonymous_variant	3/20	1
AFF2	ENST00000370458.5	c.282A>G	p.Pro94=	synonymous_variant	3/8	1

Frequencies

GnomAD3 genomes AF: 0.000232 AC: 26 AN: 111898 Hom.: 0 Cov.: 23 AF XY: 0.0000881 AC XY: 3 AN XY: 34050

Gnomad AFR AF: 0.0000974

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000432

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000213 AC: 39 AN: 183470 Hom.: 1 AF XY: 0.000221 AC XY: 15 AN XY: 67914

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000187

Gnomad NFE exome AF: 0.000415

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000398 AC: 437 AN: 1097180 Hom.: 1 Cov.: 30 AF XY: 0.000372 AC XY: 135 AN XY: 362570

Gnomad4 AFR exome AF: 0.0000758

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000173

Gnomad4 NFE exome AF: 0.000481

Gnomad4 OTH exome AF: 0.000478

GnomAD4 genome AF: 0.000232 AC: 26 AN: 111898 Hom.: 0 Cov.: 23 AF XY: 0.0000881 AC XY: 3 AN XY: 34050

Gnomad4 AFR AF: 0.0000974

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000432

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000218 Hom.: 1

Bravo AF: 0.000215

EpiCase AF: 0.000218

EpiControl AF: 0.000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	9.2
Dann	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs370409032; hg19: chrX-147743542;