X-148837678-C-T

Variant names:

• chrX-148837678-C-T
• rs587780276
• NM_002025.4:c.1118C>T

Variant summary

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

The NM_002025.4(AFF2):​c.1118C>T​(p.Thr373Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. T373S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: AFF2 NM_002025.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.49
• 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, Labcorp Genetics (formerly Invitae), G2P
• 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.1118C>T	p.Thr373Ile	missense	Exon 5 of 21	NP_002016.2	P51816-1
	AFF2	NM_001169123.2		c.1106C>T	p.Thr369Ile	missense	Exon 5 of 21	NP_001162594.1	P51816-5
	AFF2	NM_001169122.2		c.1075-5288C>T		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.1118C>T	p.Thr373Ile	missense	Exon 5 of 21	ENSP00000359489.2	P51816-1
	AFF2	ENST00000342251.7	TSL:1	c.1075-5288C>T		intron	N/A	ENSP00000345459.4	P51816-3
	AFF2	ENST00000370457.9	TSL:1	c.1087-5288C>T		intron	N/A	ENSP00000359486.6	P51816-6

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-0.41	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		2.5
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.55
Sift	Benign	0.058	T
Sift4G	Benign	0.068	T
Polyphen		0.90	P
Vest4		0.46
MutPred		0.54		Loss of phosphorylation at T373 (P = 0.0182)
MVP		0.80
MPC		0.63
ClinPred		0.98	D
GERP RS		4.6
Varity_R		0.26
gMVP		0.72
Mutation Taster		=56/44	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: rs587780276; hg19: chrX-147919202;