chrX-148661902-T-C

Variant names:

• chrX-148661902-T-C
• rs797044705
• NM_002025.4:c.181-6T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002025.4(AFF2):​c.181-6T>C variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00000897 in 111,510 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 9.3e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: AFF2 NM_002025.4 splice_region, intron
• Scores: Splicing: ADA: 0.0002862
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.69
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFF2	NM_002025.4	c.181-6T>C		splice_region_variant, intron_variant	Intron 2 of 20	ENST00000370460.7	NP_002016.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFF2	ENST00000370460.7	c.181-6T>C		splice_region_variant, intron_variant	Intron 2 of 20	5	NM_002025.4	ENSP00000359489.2
AFF2	ENST00000342251.7	c.169-6T>C		splice_region_variant, intron_variant	Intron 2 of 19	1		ENSP00000345459.4
AFF2	ENST00000370457.9	c.181-6T>C		splice_region_variant, intron_variant	Intron 2 of 19	1		ENSP00000359486.6
AFF2	ENST00000370458.5	c.169-6T>C		splice_region_variant, intron_variant	Intron 2 of 7	1		ENSP00000359487.1

Frequencies

GnomAD3 genomes AF: 0.00000897 AC: 1 AN: 111510 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000326

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000125 AC: 2 AN: 160292 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000183

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000135

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.33e-7 AC: 1 AN: 1071586 Hom.: 0 Cov.: 30 AF XY: 0.00000288 AC XY: 1 AN XY: 346826

African (AFR) AF: 0.00 AC: 0 AN: 25068

American (AMR) AF: 0.00 AC: 0 AN: 30928

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17977

East Asian (EAS) AF: 0.00 AC: 0 AN: 29952

South Asian (SAS) AF: 0.00 AC: 0 AN: 50452

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39801

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3984

European-Non Finnish (NFE) AF: 0.00000121 AC: 1 AN: 828575

Other (OTH) AF: 0.00 AC: 0 AN: 44849

GnomAD4 genome AF: 0.00000897 AC: 1 AN: 111510 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33678

African (AFR) AF: 0.0000326 AC: 1 AN: 30690

American (AMR) AF: 0.00 AC: 0 AN: 10495

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3545

South Asian (SAS) AF: 0.00 AC: 0 AN: 2637

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6001

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53083

Other (OTH) AF: 0.00 AC: 0 AN: 1495

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 15, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	14
DANN	Benign	0.77
PhyloP100		3.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00029
dbscSNV1_RF	Benign	0.010
SpliceAI score (max)		0.010		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: rs797044705; hg19: chrX-147743423;