rs797045218

Variant names:

• chrX-148837693-C-G
• rs797045218
• NM_002025.4:c.1133C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002025.4(AFF2):​c.1133C>G​(p.Ala378Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: AFF2 NM_002025.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.26
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17170149).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFF2	NM_002025.4	MANE Select	c.1133C>G	p.Ala378Gly	missense	Exon 5 of 21	NP_002016.2
	AFF2	NM_001169123.2		c.1121C>G	p.Ala374Gly	missense	Exon 5 of 21	NP_001162594.1
	AFF2	NM_001169122.2		c.1075-5273C>G		intron	N/A	NP_001162593.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFF2	ENST00000370460.7	TSL:5 MANE Select	c.1133C>G	p.Ala378Gly	missense	Exon 5 of 21	ENSP00000359489.2
	AFF2	ENST00000342251.7	TSL:1	c.1075-5273C>G		intron	N/A	ENSP00000345459.4
	AFF2	ENST00000370457.9	TSL:1	c.1087-5273C>G		intron	N/A	ENSP00000359486.6

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.70	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.3
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.11
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.014	D
Polyphen		0.042	B
Vest4		0.27
MutPred		0.57		Loss of catalytic residue at A378 (P = 0.0483)
MVP		0.39
MPC		0.14
ClinPred		0.44	T
GERP RS		5.4
Varity_R		0.32
gMVP		0.35
Mutation Taster		=85/15	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: rs797045218; hg19: chrX-147919217;