Variant X-148652065-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_002025.4(AFF2):c.114G>T(p.Gln38His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000919 in 1,088,424 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 9.2e-7 ( 0 hom. 0 hem. )

Consequence

AFF2
NM_002025.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.40

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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.784

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AFF2	NM_002025.4 link	c.114G>T	p.Gln38His	missense_variant	2/21	ENST00000370460.7	NP_002016.2	P51816-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
AFF2	ENST00000370460.7 link	c.114G>T	p.Gln38His	missense_variant	2/21	5	NM_002025.4	ENSP00000359489.2	P51816-1
AFF2	ENST00000342251.7 link	c.114G>T	p.Gln38His	missense_variant	2/20	1		ENSP00000345459.4	P51816-3
AFF2	ENST00000370457.9 link	c.114G>T	p.Gln38His	missense_variant	2/20	1		ENSP00000359486.6	P51816-6
AFF2	ENST00000370458.5 link	c.114G>T	p.Gln38His	missense_variant	2/8	1		ENSP00000359487.1	P51816-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.19e-7

AC:

AN:

1088424

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

354206

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:

0.00000120

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

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 28, 2022

The c.114G>T (p.Q38H) alteration is located in exon 2 (coding exon 2) of the AFF2 gene. This alteration results from a G to T substitution at nucleotide position 114, causing the glutamine (Q) at amino acid position 38 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.022

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;.;.;.

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.78

T;T;T;T

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.78

D;D;D;D

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.2

L;L;L;L

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.8

D;D;D;D

REVEL

Uncertain

0.42

Sift

Benign

0.11

T;D;T;D

Sift4G

Benign

0.28

T;T;T;T

Polyphen

1.0

D;D;D;D

Vest4

0.47

MutPred

0.72

Loss of disorder (P = 0.152);Loss of disorder (P = 0.152);Loss of disorder (P = 0.152);Loss of disorder (P = 0.152);

MVP

0.72

MPC

0.59

ClinPred

0.99

GERP RS

3.6

Varity_R

0.54

gMVP

0.45

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