NM_002025.4:c.114G>T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 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

Publications

0 publications found

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 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

AFF2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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 rank	MANE	Protein	UniProt
AFF2	NM_002025.4 link	c.114G>T	p.Gln38His	missense_variant	Exon 2 of 21	ENST00000370460.7	NP_002016.2	P51816-1

Ensembl

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

African (AFR)

AF:

0.00

AC:

AN:

26200

American (AMR)

AF:

0.00

AC:

AN:

35150

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19303

East Asian (EAS)

AF:

0.00

AC:

AN:

30132

South Asian (SAS)

AF:

0.00

AC:

AN:

53812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40512

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4103

European-Non Finnish (NFE)

AF:

0.00000120

AC:

AN:

833441

Other (OTH)

AF:

0.00

AC:

AN:

45771

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Apr 28, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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

PhyloP100

1.4

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

Mutation Taster

=37/63

disease causing

(source)

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

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NM_002025.4:c.114G>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over