X-148661983-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002025.4(AFF2):c.256A>C(p.Thr86Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000183 in 1,095,360 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: AFF2 NM_002025.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.01

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4135028).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AFF2	NM_002025.4	c.256A>C	p.Thr86Pro	missense_variant	3/21	ENST00000370460.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AFF2	ENST00000370460.7	c.256A>C	p.Thr86Pro	missense_variant	3/21	5	NM_002025.4	P1
AFF2	ENST00000342251.7	c.244A>C	p.Thr82Pro	missense_variant	3/20	1
AFF2	ENST00000370457.9	c.256A>C	p.Thr86Pro	missense_variant	3/20	1
AFF2	ENST00000370458.5	c.244A>C	p.Thr82Pro	missense_variant	3/8	1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1095360 Hom.: 0 Cov.: 30 AF XY: 0.00000277 AC XY: 1 AN XY: 360856

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000238

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 01, 2020

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D;.;.;.
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Uncertain	0.089	D
MetaRNN	Benign	0.41	T;T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.5	M;.;.;M
MutationTaster	Benign	0.84	D;D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-4.1	D;D;D;.
REVEL	Uncertain	0.42
Sift	Uncertain	0.0060	D;D;D;.
Sift4G	Benign	0.19	T;T;D;T
Polyphen		0.93	P;P;D;P
Vest4		0.34
MutPred		0.67		Gain of disorder (P = 0.1049);.;.;Gain of disorder (P = 0.1049);
MVP		0.64
MPC		0.43
ClinPred		0.99	D
GERP RS		3.0
Varity_R		0.79
gMVP		0.60

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-147743504;