chrX-148501124-C-T

Variant names:

• chrX-148501124-C-T
• rs781966000
• NM_002025.4:c.27C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_002025.4(AFF2):​c.27C>T​(p.Asp9Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000165 in 1,209,877 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. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: AFF2 NM_002025.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.19
• 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant X-148501124-C-T is Benign according to our data. Variant chrX-148501124-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1796176.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.19 with no splicing effect.

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.27C>T	p.Asp9Asp	synonymous	Exon 1 of 21	NP_002016.2	P51816-1
	AFF2	NM_001169123.2		c.27C>T	p.Asp9Asp	synonymous	Exon 1 of 21	NP_001162594.1	P51816-5
	AFF2	NM_001169122.2		c.27C>T	p.Asp9Asp	synonymous	Exon 1 of 20	NP_001162593.1	P51816-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFF2	ENST00000370460.7	TSL:5 MANE Select	c.27C>T	p.Asp9Asp	synonymous	Exon 1 of 21	ENSP00000359489.2	P51816-1
	AFF2	ENST00000342251.7	TSL:1	c.27C>T	p.Asp9Asp	synonymous	Exon 1 of 20	ENSP00000345459.4	P51816-3
	AFF2	ENST00000370457.9	TSL:1	c.27C>T	p.Asp9Asp	synonymous	Exon 1 of 20	ENSP00000359486.6	P51816-6

Frequencies

GnomAD3 genomes AF: 0.00000889 AC: 1 AN: 112523 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000323

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: 0.00000553 AC: 1 AN: 180673 AF XY: 0.00

Gnomad AFR exome AF: 0.0000765

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097354 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 362926

African (AFR) AF: 0.00 AC: 0 AN: 26362

American (AMR) AF: 0.00 AC: 0 AN: 35173

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19348

East Asian (EAS) AF: 0.00 AC: 0 AN: 30158

South Asian (SAS) AF: 0.00 AC: 0 AN: 54113

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4127

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841636

Other (OTH) AF: 0.00 AC: 0 AN: 46039

GnomAD4 genome AF: 0.00000889 AC: 1 AN: 112523 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34705

African (AFR) AF: 0.0000323 AC: 1 AN: 30943

American (AMR) AF: 0.00 AC: 0 AN: 10773

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2656

East Asian (EAS) AF: 0.00 AC: 0 AN: 3546

South Asian (SAS) AF: 0.00 AC: 0 AN: 2718

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6211

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53236

Other (OTH) AF: 0.00 AC: 0 AN: 1516

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	15
DANN	Benign	0.97
PhyloP100		2.2
PromoterAI		-0.0042	Neutral

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: rs781966000; hg19: chrX-147582644;