X-148962804-G-T

Variant names:

• chrX-148962804-G-T
• rs140927355
• NM_002025.4:c.2780G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002025.4(AFF2):​c.2780G>T​(p.Arg927Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000893 in 111,939 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R927H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: AFF2 NM_002025.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.61
• Publications: 5 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.2780G>T	p.Arg927Leu	missense	Exon 13 of 21	NP_002016.2
	AFF2	NM_001169123.2		c.2750G>T	p.Arg917Leu	missense	Exon 13 of 21	NP_001162594.1
	AFF2	NM_001169122.2		c.2681G>T	p.Arg894Leu	missense	Exon 12 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.2780G>T	p.Arg927Leu	missense	Exon 13 of 21	ENSP00000359489.2
	AFF2	ENST00000342251.7	TSL:1	c.2681G>T	p.Arg894Leu	missense	Exon 12 of 20	ENSP00000345459.4
	AFF2	ENST00000370457.9	TSL:1	c.2675G>T	p.Arg892Leu	missense	Exon 12 of 20	ENSP00000359486.6

Frequencies

GnomAD3 genomes AF: 0.00000893 AC: 1 AN: 111939 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

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

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.12e-7 AC: 1 AN: 1096223 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 1 AN XY: 361705

African (AFR) AF: 0.00 AC: 0 AN: 26353

American (AMR) AF: 0.00 AC: 0 AN: 35190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19370

East Asian (EAS) AF: 0.00 AC: 0 AN: 30187

South Asian (SAS) AF: 0.00 AC: 0 AN: 54060

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40523

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 840373

Other (OTH) AF: 0.00 AC: 0 AN: 46034

GnomAD4 genome AF: 0.00000893 AC: 1 AN: 111939 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34125

African (AFR) AF: 0.00 AC: 0 AN: 30764

American (AMR) AF: 0.00 AC: 0 AN: 10525

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3595

South Asian (SAS) AF: 0.00 AC: 0 AN: 2657

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6094

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53225

Other (OTH) AF: 0.00 AC: 0 AN: 1512

Alfa AF: 0.00 Hom.: 51

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.6
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.30
MutPred		0.41		Loss of glycosylation at P924 (P = 0.0658)
MVP		0.79
MPC		0.57
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.48
gMVP		0.44
Mutation Taster		=66/34	polymorphism

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: rs140927355; hg19: chrX-148044334;