chrX-148956472-A-G

Variant names:

• chrX-148956472-A-G
• rs782571214
• NM_002025.4:c.2427A>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_002025.4(AFF2):​c.2427A>G​(p.Leu809Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,209,654 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 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 0.000018 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000015 (0 hom. 6 hem.)
• Consequence: AFF2 NM_002025.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.270
• Publications: 1 publications found

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

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant X-148956472-A-G is Benign according to our data. Variant chrX-148956472-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 434097.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.27 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome4 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFF2	NM_002025.4	MANE Select	c.2427A>G	p.Leu809Leu	synonymous	Exon 11 of 21	NP_002016.2
	AFF2	NM_001169123.2		c.2397A>G	p.Leu799Leu	synonymous	Exon 11 of 21	NP_001162594.1
	AFF2	NM_001169122.2		c.2328A>G	p.Leu776Leu	synonymous	Exon 10 of 20	NP_001162593.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFF2	ENST00000370460.7	TSL:5 MANE Select	c.2427A>G	p.Leu809Leu	synonymous	Exon 11 of 21	ENSP00000359489.2
	AFF2	ENST00000342251.7	TSL:1	c.2328A>G	p.Leu776Leu	synonymous	Exon 10 of 20	ENSP00000345459.4
	AFF2	ENST00000370457.9	TSL:1	c.2322A>G	p.Leu774Leu	synonymous	Exon 10 of 20	ENSP00000359486.6

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111435 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000327

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000545 AC: 1 AN: 183427 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000146 AC: 16 AN: 1098219 Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 6 AN XY: 363573

African (AFR) AF: 0.00 AC: 0 AN: 26403

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54147

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.0000166 AC: 14 AN: 842104

Other (OTH) AF: 0.0000434 AC: 2 AN: 46096

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111435 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33667

African (AFR) AF: 0.0000327 AC: 1 AN: 30614

American (AMR) AF: 0.00 AC: 0 AN: 10518

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3548

South Asian (SAS) AF: 0.00 AC: 0 AN: 2619

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6013

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53052

Other (OTH) AF: 0.00 AC: 0 AN: 1507

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	4.6
DANN	Benign	0.80
PhyloP100		0.27

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

Other links and lift over

dbSNP: rs782571214; hg19: chrX-148038002;