Variant X-148661983-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.01

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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	Protein	UniProt
AFF2	NM_002025.4 link	c.256A>C	p.Thr86Pro	missense_variant	3/21	ENST00000370460.7	NP_002016.2	P51816-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
AFF2	ENST00000370460.7 link	c.256A>C	p.Thr86Pro	missense_variant	3/21	5	NM_002025.4	ENSP00000359489.2	P51816-1
AFF2	ENST00000342251.7 link	c.244A>C	p.Thr82Pro	missense_variant	3/20	1		ENSP00000345459.4	P51816-3
AFF2	ENST00000370457.9 link	c.256A>C	p.Thr86Pro	missense_variant	3/20	1		ENSP00000359486.6	P51816-6
AFF2	ENST00000370458.5 link	c.244A>C	p.Thr82Pro	missense_variant	3/8	1		ENSP00000359487.1	P51816-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000183

AC:

AN:

1095360

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

360856

show subpopulations

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.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

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

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.65

D;.;.;.

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.92

D;D;D;D

M_CAP

Uncertain

0.089

MetaRNN

Benign

0.41

T;T;T;T

MetaSVM

Benign

-0.67

MutationAssessor

Uncertain

2.5

M;.;.;M

PrimateAI

Benign

0.48

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over