rs1076374

Variant names:

• chrX-148983825-G-A
• rs1076374
• NM_002025.4:c.3623+3035G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-148983825-G-A
• chrX-148983825-G-C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002025.4(AFF2):​c.3623+3035G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.91 (32905 hom., 27013 hem., cov: 20)
  • Failed GnomAD Quality Control
• Consequence: AFF2 NM_002025.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.918
• 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, Labcorp Genetics (formerly Invitae), G2P
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).

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.3623+3035G>A		intron	N/A	NP_002016.2	P51816-1
	AFF2	NM_001169123.2		c.3593+3035G>A		intron	N/A	NP_001162594.1	P51816-5
	AFF2	NM_001169122.2		c.3518+3035G>A		intron	N/A	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.3623+3035G>A		intron	N/A	ENSP00000359489.2	P51816-1
	AFF2	ENST00000342251.7	TSL:1	c.3518+3035G>A		intron	N/A	ENSP00000345459.4	P51816-3
	AFF2	ENST00000370457.9	TSL:1	c.3518+3035G>A		intron	N/A	ENSP00000359486.6	P51816-6

Frequencies

GnomAD3 genomes AF: 0.914 AC: 97849 AN: 107071 Hom.: 32911 Cov.: 20

Gnomad AFR AF: 0.724

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.947

Gnomad ASJ AF: 0.980

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.997

Gnomad FIN AF: 0.998

Gnomad MID AF: 0.952

Gnomad NFE AF: 0.992

Gnomad OTH AF: 0.915

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.914 AC: 97881 AN: 107119 Hom.: 32905 Cov.: 20 AF XY: 0.916 AC XY: 27013 AN XY: 29497

African (AFR) AF: 0.724 AC: 21284 AN: 29384

American (AMR) AF: 0.947 AC: 9304 AN: 9827

Ashkenazi Jewish (ASJ) AF: 0.980 AC: 2543 AN: 2595

East Asian (EAS) AF: 1.00 AC: 3392 AN: 3393

South Asian (SAS) AF: 0.999 AC: 2278 AN: 2281

European-Finnish (FIN) AF: 0.998 AC: 5242 AN: 5255

Middle Eastern (MID) AF: 0.952 AC: 200 AN: 210

European-Non Finnish (NFE) AF: 0.992 AC: 51637 AN: 52052

Other (OTH) AF: 0.916 AC: 1324 AN: 1445

Alfa AF: 0.955 Hom.: 22557

Bravo AF: 0.903

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.11
DANN	Benign	0.73
PhyloP100		-0.92
Mutation Taster		=100/0	polymorphism (auto)

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: rs1076374; hg19: chrX-148065355;